相关论文
2010 - IEEE Sensors Journal
Optimal Frequency Range Selection for PZT Transducers in Impedance-Based SHM Systems

Piezoelectric transducers of PZT (lead zirconate titanate) have been widely used in structural health monitoring (SHM) systems based on the electromechanical (E/M) impedance technique. In this technique, damages in the structure are identified by measuring the electrical impedance of the transducer in an appropriate frequency range. Usually, the selection of the correct frequency range to detect and evaluate damage is obtained by trial and error methods. In this paper, it is proposed a formal procedure to determine the frequency ranges in which the PZT transducers are more sensitive for damage detection. Tests were carried out on specimens with different sizes and there was a good match between the theoretical and practical results.

1993 - Proceedings of the National Academy of Sciences of the United States of America
Guanosine binding to the Tetrahymena ribozyme: thermodynamic coupling with oligonucleotide binding.

The L-21 Sca I ribozyme derived from the group I intron of Tetrahymena thermophila pre-rRNA catalyzes an endonuclease reaction analogous to the first step of self-splicing. Guanosine (G) is bound by the ribozyme, and its 3'-hydroxyl group acts as the nucleophile. Here, we provide evidence that Km for G in several single-turnover reactions is equal to the equilibrium dissociation constant for G. This evidence includes the observation that removal of the 2'-hydroxyl group at the cleavage site of the oligoribonucleotide substrate [from CCCUCUA to CCCUC(dU)A] decreases the rate of cleavage approximately 1000-fold but has no effect on either the Km for G (0.17 mM) or for guanosine 5'-monophosphate (pG) (0.09 mM). In the course of this study, it was observed that Km for G or pG was lower by a factor of 5 for reactions with the ribozyme-CCCUC(dU)A complex compared with the free ribozyme, indicating a modest amount of thermodynamic coupled binding of the two substrates. The decrease in the rate of oligonucleotide dissociation upon addition of saturating pG provides independent support for this coupling. Coupling is lost with a substrate that cannot make the normal tertiary interactions with the ribozyme, providing evidence that coupled binding requires docking of the substrate into the catalytic core. Surprisingly, the binding of product CCCUCU and G is slightly anticooperative, indicating that the cleaved pA is important for coupling with substrate. Coupled binding suggests a splicing model in which the intron binds G tightly to promote the first step of reaction, after which its binding is an order of magnitude weaker, thereby facilitating the second step.

1993 - Journal of virology
Divergence and evolution of homologous regions of Bombyx mori nuclear polyhedrosis virus

Homologous regions (hrs) (hr1,hr2-left,hr2-right,hr3,hr4-left,hr 4-right, and hr5) similar to those found in the Autographa californica nuclear polyhedrosis virus (AcNPV) genome were found in the Bombyx mori NPV (BmNPV) genome. The BmNPV hrs contained two to eight repeats of a homologous nucleotide sequence which were on average about 75 bp long. All of these homologous sequence repeats contained a 26-bp-long palindrome motif with an EcoRI or EcoRI-like site at its core. The consensus sequence of the BmNPV hrs showed 95% conservation with respect to those found in AcNPV. Nucleotide sequence analysis indicated that hr2-left and hr2-right of BmNPV evolved from an ancestor similar to hr2 of AcNPV by inversion, cleavage, and ligation. The polarities of the BmNPV and AcNPV hrs were conserved except for that of hr4-left. Within hr4-right of BmNPV, four repeats of a previously underscribed palindrome motif were found. Bmhr5D, a BmNPV mutant which lacked hr5, replicated at a rate similar to that of wild-type BmNPV in BmN cells and silkworm larvae, indicating that hr5 was not essential for viral replication. After ten passages of Bmhr5D in BmN cells, no detectable changes in its genome were observed by restriction endonuclease analysis. The evolution and divergence of the BmNPV genome are also discussed.

2001 - The Journal of comparative neurology
Neuronal body size correlates with the number of nucleoli and Cajal bodies, and with the organization of the splicing machinery in rat trigeminal ganglion neurons

Trigeminal ganglion neurons comprise three main cell body‐size types. This cell size heterogeneity provides an excellent neuronal model to study the cell size‐dependent organization and dynamics of the nucleoli, Cajal (coiled) bodies (CBs), and nuclear speckles of pre‐mRNA splicing factors, nuclear structures that play a key role in the normal neuronal physiology. We have analyzed the number of nucleoli and CBs and the structural and molecular organization of CBs and nuclear speckles in the three neuronal types by using immunofluorescence with antibodies that recognize nucleoli (fibrillarin), CBs (coilin), and nuclear speckles (snRNPs), confocal microscopy, and electron microscopy. Whereas the mean number of nucleoli per neuron decreases as a function of cell size, the number of CBs per cell significantly increases in large neurons in comparison with the small ones. In addition, large neurons have a higher proportion of CBs associated with the nucleolus. In all neuronal types, CBs concentrate coilin, fibrillarin, snRNPs, and the survival motor neuron protein (SMN). Immunostaining for snRNPs shows small speckle domains and extensive areas of diffuse nucleoplasmic signal in large neurons, in contrast with the large nuclear speckles found in small neurons. Furthermore, flow cytometric analysis shows that all neurons are in the range of diploid cells. These findings indicate that the fusion behavior of nucleoli, the formation of CBs and their relationships with the nucleolus, as well as the compartmentalization of the pre‐mRNA splicing machinery, is related to cell body size in the trigeminal ganglion neurons. Because transcriptional activity is a basic determinant mechanism of cell size in diploid cells, we suggest that our findings reflect a distinct transcription‐dependent organization of the nucleolus and splicing machinery in the three cell types of trigeminal ganglion neurons. J. Comp. Neurol. 430:250–263, 2001. © 2001 Wiley‐Liss, Inc.

1999 - Biochemical and biophysical research communications
APOBEC-2, a cardiac- and skeletal muscle-specific member of the cytidine deaminase supergene family.

APOBEC-1, which mediates the editing of apolipoprotein (apo) B mRNA, is the only known member of the C (cytidine)-->U (uridine) editing enzyme subfamily of the cytidine deaminase supergene family. Here we report the cloning of APOBEC-2, another member of the subfamily. Human and mouse APOBEC-2 both contain 224 amino acid residues, and their genes are mapped to syntenic regions of human chromosome 6 (6p21) and mouse chromosome 17. By phylogenetic analysis, APOBEC-2 is shown to be evolutionarily related to APOBEC-1, and analysis of substitution rates indicates that APOBEC-2 is a much better conserved gene than APOBEC-1. APOBEC-2 mRNA and protein are expressed exclusively in heart and skeletal muscle. APOBEC-2 does not display detectable apoB mRNA editing activity. Like other editing enzymes of the cytidine deaminase superfamily, APOBEC-2 has low, but definite, intrinsic cytidine deaminase activity. The identification of APOBEC-2 indicates that APOBEC-1 is not the only member of the C-->U editing enzyme subfamily, which, like the A (adenosine)-->I (inosine) subfamily of editing enzymes, must encompass at least two and possibly more different deaminase enzymes. It suggests that the C-->U editing affecting apoB mRNA and other RNAs is not an isolated event mediated by a single enzyme but involves multiple related proteins that have evolved from a primordial gene closely related to the housekeeping enzyme cytidine deaminase.

1986 - Proceedings of the National Academy of Sciences of the United States of America
Mechanism of DNA polymerase I: exonuclease/polymerase activity switch and DNA sequence dependence of pyrophosphorolysis and misincorporation reactions.

Mechanistic features of several processes involved in the idling-turnover reaction catalyzed by the large (Klenow) fragment of Escherichia coli DNA polymerase I have been established. The exonuclease----polymerase activity switch involved in the excision/incorporation mode of idling-turnover occurs without an intervening dissociation of the enzyme from its DNA substrate. Comparative studies on the pyrophosphorolysis kinetics of related DNA substrates indicate a significant dependence of the reaction rate upon the DNA sequence within the duplex region upstream of the primer-template junction. Finally, a gel electrophoretic analysis of the products of the idling-turnover reaction has provided direct evidence for an alternative DNA sequence-dependent misincorporation/excision pathway.

2013 - Anticancer research
DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer.

The DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are the most successful epigenetic drugs to date and are still the most widely used as epigenetic modulators, even though their application for oncological diseases is restricted by their relative toxicity and poor chemical stability. Zebularine (1-(β-D-ribofuranosyl)-1,2-dihydropyrimidin-2-one), a more stable and less toxic cytidine analog, is another inhibitor of DNMT with concomitant inhibitory activity towards cytidine deaminase. Unfortunately, there is no new information related to the possible clinical applications of zebularine. Although many new inhibitors of DNMT have been identified, none of them can so far replace azacytidine, decitabine and, to a lesser degree, zebularine. This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy. We also discuss the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles, reflecting their complex and partially overlapping biological effects.

2011 - Human molecular genetics
Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas are neuroendocrine tumors that occur in the context of inherited cancer syndromes in ∼30% of cases and are linked to germline mutations in the VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127 genes. Although genome-wide expression studies have revealed some of the mechanisms likely to be involved in pheochromocytoma/paraganglioma tumorigenesis, the complete molecular distinction of all subtypes of hereditary tumors has not been solved and the genetic events involved in the generation of sporadic tumors are unknown. With these purposes in mind, we investigated 202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, using expression profiling, BAC array comparative genomic hybridization and somatic mutation screening. Gene expression signatures defined the hereditary tumors according to their genotype and notably, led to a complete subseparation between SDHx- and VHL-related tumors. In tumor tissues, the systematic characterization of somatic genetic events associated with germline mutations in tumor suppressor genes revealed loss of heterozygosity (LOH) in a majority of cases, but also detected point mutations and copy-neutral LOH. Finally, guided by transcriptome classifications and LOH profiles, somatic mutations in VHL or RET genes were identified in 14% of sporadic pheochromocytomas/paragangliomas. Overall, we found a germline or somatic genetic alteration in 45.5% (92/202) of the tumors in this large series of pheochromocytomas/paragangliomas. Regarding mutated genes, specific molecular pathways involved in tumorigenesis mechanisms are identified. Altogether, these new findings suggest that somatic mutation analysis is likely to yield important clues for personalizing molecular targeted therapies.

2017 - Journal of pineal research
Melatonin: A pleiotropic molecule that modulates DNA damage response and repair pathways

DNA repair is responsible for maintaining the integrity of the genome. Perturbations in the DNA repair pathways have been identified in several human cancers. Thus, compounds targeting DNA damage response (DDR) hold great promise in cancer therapy. A great deal of effort, in pursuit of new anticancer drugs, has been devoted to understanding the basic mechanisms and functions of the cellular DNA repair machinery. Melatonin, a widely produced indoleamine in all organisms, is associated with a reduced risk of cancer and has multiple regulatory roles on the different aspects of the DDR and DNA repair. Herein, we have mainly discussed how defective components in different DNA repair machineries, including homologous recombination (HR), nonhomologous end‐joining (NHEJ), base excision repair (BER), nucleotide excision repair (NER), and finally DNA mismatch repair (MMR), can contribute to the risk of cancer. Melatonin biosynthesis, mode of action, and antioxidant effects are reviewed along with the means by which the indoleamine regulates DDR at the transduction, mediation, and functional levels. Finally, we summarize recent studies that illustrate how melatonin can be combined with DNA‐damaging agents to improve their efficacy in cancer therapy.

2015 - The British journal of surgery
Sinistral portal hypertension after pancreaticoduodenectomy with splenic vein ligation

Splenic vein ligation may result in sinistral (left‐sided) portal hypertension and gastrointestinal haemorrhage. The aim of this study was to analyse the pathogenesis of sinistral portal hypertension following splenic vein ligation in pancreaticoduodenectomy.

1996 - The EMBO journal
Cross‐linking CD40 on B cells preferentially induces stress‐activated protein kinases rather than mitogen‐activated protein kinases.

The B cell‐associated surface molecule CD40 plays a key role in T cell‐dependent B cell maturation, as individuals with defects in either CD40 or its ligand are impaired in immunoglobulin isotype class switching and germinal center formation. CD40 signaling activates downstream effectors, including the tyrosine protein kinase, Lyn, the phosphatidylinositol‐3‐kinase (PI‐3 kinase), and the transcription factor, NF‐kappa B. In this study, we demonstrate that stress‐activated protein kinases (SAPK) are activated after CD40 cross‐linking on various B cell lines or human tonsillar B cells. The activation is rapid and transient and is mediated through a cyclosporin A‐insensitive pathway. Furthermore, this signaling pathway appears not to rely on protein kinase C. While CD40 ligation strongly activates the SAPKs (up to 25‐fold), it does not affect members of the mitogen‐activated protein kinase family (MAPK; ERK1 and ERK2). Consistent with these data, CD40 signals up‐regulate c‐jun but not c‐fos mRNA and alter the transcription factor ATF2 but not the Raf‐1 protein. In summary, CD40 signaling preferentially induces SAPK but not MAPK.

2004 - Proceedings of the National Academy of Sciences of the United States of America
Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut

The mechanism to maintain homeostasis of the gut microbiota remains largely unknown despite its critical role in the body defense. In the intestines of mice with deficiency of activation-induced cytidine deaminase (AID), the absence of hypermutated IgA is partially compensated for by the presence of large amounts of unmutated IgM and normal expression levels of defensins and angiogenins. We show here a predominant and persistent expansion of segmented filamentous bacteria throughout the small intestine of AID–/– mice. Reconstitution of lamina propria IgA production in AID–/– mice recovered the normal composition of gut flora and abolished the local and systemic activation of the immune system. The results indicate that secretions of IgAs rather than innate defense peptides are critical to regulation of commensal bacterial flora and that the segmented filamentous bacteria antigens are strong stimuli of the mucosal immune system.

2019 - Blood
Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

2004 - Molecular and Cellular Biology
Requirement of the Mre11 Complex and Exonuclease 1 for Activation of the Mec1 Signaling Pathway

ABSTRACT The large protein kinases, ataxia-telangiectasia mutated (ATM) and ATM-Rad3-related (ATR), orchestrate DNA damage checkpoint pathways. In budding yeast, ATM and ATR homologs are encoded by TEL1 and MEC1, respectively. The Mre11 complex consists of two highly related proteins, Mre11 and Rad50, and a third protein, Xrs2 in budding yeast or Nbs1 in mammals. The Mre11 complex controls the ATM/Tel1 signaling pathway in response to double-strand break (DSB) induction. We show here that the Mre11 complex functions together with exonuclease 1 (Exo1) in activation of the Mec1 signaling pathway after DNA damage and replication block. Mec1 controls the checkpoint responses following UV irradiation as well as DSB induction. Correspondingly, the Mre11 complex and Exo1 play an overlapping role in activation of DSB- and UV-induced checkpoints. The Mre11 complex and Exo1 collaborate in producing long single-stranded DNA (ssDNA) tails at DSB ends and promote Mec1 association with the DSBs. The Ddc1-Mec3-Rad17 complex associates with sites of DNA damage and modulates the Mec1 signaling pathway. However, Ddc1 association with DSBs does not require the function of the Mre11 complex and Exo1. Mec1 controls checkpoint responses to stalled DNA replication as well. Accordingly, the Mre11 complex and Exo1 contribute to activation of the replication checkpoint pathway. Our results provide a model in which the Mre11 complex and Exo1 cooperate in generating long ssDNA tracts and thereby facilitate Mec1 association with sites of DNA damage or replication block.

2010 - The Journal of Immunology
In Vivo Redundant Function of the 3′ IgH Regulatory Element HS3b in the Mouse

In the mouse, the regulatory region located at the 3′ end of the IgH locus includes four transcriptional enhancers: HS3a, HS1-2, HS3b, and HS4; the first three lie in a quasi-palindromic structure. Although the upstream elements HS3a and HS1-2 proved dispensable for Ig expression and class switch recombination (CSR), the joint deletion of HS3b and HS4 led to a consistent decrease in IgH expression in resting B cells and to a major CSR defect. Within this pair of distal enhancers, it was questionable whether HS3b and HS4 could be considered individually as elements critical for IgH expression and/or CSR. Studies in HS4-deficient mice recently revealed the role of HS4 as restricted to Igμ-chain expression from the pre-B to the mature B cell stage and left HS3b as the last candidate for CSR regulation. Our present study finally invalidates the hypothesis that CSR could mostly rely on HS3b itself. B cells from HS3b-deficient animals undergo normal proliferation, germline transcription, and CSR upon in vitro stimulation with LPS; in vivo Ag-specific responses are not affected. In conclusion, our study highlights a major effect of the global ambiance of the IgH locus; enhancers demonstrated as being strongly synergistic in transgenes turn out to be redundant in their endogenous context.

1992 - Surgery
Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors.

Seventy-five patients with advanced abdominal carcinoid tumors (65 midgut, 10 others) have been examined retrospectively to evaluate the role of surgical treatment as a principle, irrespective of stage of disease. Eighteen of 52 patients (35%) exhibited the carcinoid syndrome. Two or more primaries were found in 39% of patients with midgut lesion, 81% of these patients had regional metastases, 5% of these patients had distant lymph node metastases, and 74% of the patients had liver secondaries. All patients underwent operation, an additional 34% of the patients had a further reoperation, 9% of the patients had a second reoperation, 3% of the patients had a third reoperation, and one patient (2%) had a fourth reoperation. Intraoperative debulking (liver excluded) was performed in 33% of the patients, and 48% of the patients had treatment (resection, hepatic artery ligation, embolization) directed at the liver. The postoperative mortality rate was 2% after the primary operation for midgut lesions. The median survival for midgut tumors was 92 months, compared to 40 months for other lesions (not significant). A significantly higher survival rate was revealed for those patients with midgut lesion who were undergoing intraabdominal debulking procedures (liver excluded); median survival was 139 months versus 69 months without debulking. For those patients with liver metastases, median survival after intervention was 216 months and 48 months without such treatment (p less than 0.001). It is concluded that resection of intraabdominal carcinoid tumor masses can be performed in a high proportion of patients. Despite the retrospective, uncontrolled nature of this study, the difference in survival probabilities in favor of aggressive surgical therapy is so marked that it is not unreasonable to conclude that surgery has played a role in prolonging life in these patients.

2000
Polynucleotide phosphorylase functions both as a 3′ → 5′ exonuclease and a poly(A) polymerase in Escherichia coli

Abstract In vitro, polynucleotide phosphorylase of Escherichia coli can both synthesize RNA by using nucleotide diphosphates as precursors and exonucleolytically degrade RNA in the presence of inorganic phosphate. However, because of the high in vivo concentration of inorganic phosphate in exponentially growing cells, it has been assumed that the enzyme works exclusively as an exonuclease. Here we demonstrate that, contrary to this prediction, polynucleotide phosphorylase not only synthesizes long, highly heteropolymeric tails in vivo, but also accounts for all of the observed residual polyadenylylation in poly(A) polymerase I deficient strains. In addition, the enzyme is responsible for adding the C and U residues that are found in poly(A) tails in exponentially growing cultures of wild type E. coli.

2005 - The Journal of experimental medicine
The very 5′ end and the constant region of Ig genes are spared from somatic mutation because AID does not access these regions

Somatic hypermutation (SHM) is restricted to VDJ regions and their adjacent flanks in immunoglobulin (Ig) genes, whereas constant regions are spared. Mutations occur after about 100 nucleotides downstream of the promoter and extend to 1–2 kb. We have asked why the very 5′ and most of the 3′ region of Ig genes are unmutated. Does the activation-induced cytosine deaminase (AID) that initiates SHM not gain access to these regions, or does AID gain access, but the resulting uracils are repaired error-free because error-prone repair does not gain access? The distribution of mutations was compared between uracil DNA glycosylase (Ung)-deficient and wild-type mice in endogenous Ig genes and in an Ig transgene. If AID gains access to the 5′ and 3′ regions that are unmutated in wild-type mice, one would expect an “AID footprint,” namely transition mutations from C and G in Ung-deficient mice in the regions normally devoid of SHM. We find that the distribution of total mutations and transitions from C and G is indistinguishable in wild-type and Ung-deficient mice. Thus, AID does not gain access to the 5′ and constant regions of Ig genes. The implications for the role of transcription and Ung in SHM are discussed.

2006 - Human mutation
Activation‐induced cytidine deaminase: structure–function relationship as based on the study of mutants

Activation‐induced cytidine deaminase (AID; gene symbol AICDA) is the key molecule required to induce immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM) of the variable regions of Ig genes. Its deficiency causes a form of hyper‐IgM (HIGM) syndrome. The study of natural AID mutants associated with HIGM as well as engineered mutants led to the characterization of the active domains of the protein. AID, through its cytidine deaminase activity, induces a targeted DNA lesion as an early step required for both CSR and SHM. Besides its cytidine deaminase activity, AID plays a further essential role in CSR, likely by recruiting CSR‐specific cofactors by its C‐terminus. A similar binding of SHM‐specific cofactors to the N‐terminal part is suggested by the functional characteristics of Nter AID artificial mutants. These data require confirmation in vivo. Finally, AID acts as a homo‐, di‐, or multimeric complex. Together, these data strongly suggest that AID, a master molecule for antibody diversification, exerts its activity on CSR not only as a cytidine deaminase enzyme but also as a docking protein, recruiting specific cofactors to a multimeric complex. Hum Mutat 27(12), 1185–1191, 2006. © 2006 Wiley‐Liss, Inc.

2002 - The Journal of Experimental Medicine
Activation-induced Deaminase (AID)-directed Hypermutation in the Immunoglobulin Sμ Region

Somatic hypermutation (SHM) and class switch recombination (CSR) cause distinct genetic alterations at different regions of immunoglobulin genes in B lymphocytes: point mutations in variable regions and large deletions in S regions, respectively. Yet both depend on activation-induced deaminase (AID), the function of which in the two reactions has been an enigma. Here we report that B cell stimulation which induces CSR but not SHM, leads to AID-dependent accumulation of SHM-like point mutations in the switch μ region, uncoupled with CSR. These findings strongly suggest that AID itself or a single molecule generated by RNA editing function of AID may mediate a common step of SHM and CSR, which is likely to be involved in DNA cleavage.

Molecular mechanism of class switch recombination: linkage with somatic hypermutation.

T. Honjo
|
M. Muramatsu
|
K. Kinoshita

Abstract:Class switch recombination (CSR) and somatic hypermutation (SHM) have been considered to be mediated by different molecular mechanisms because both target DNAs and DNA modification products are quite distinct. However, involvement of activation-induced cytidine deaminase (AID) in both CSR and SHM has revealed that the two genetic alteration mechanisms are surprisingly similar. Accumulating data led us to propose the following scenario: AID is likely to be an RNA editing enzyme that modifies an unknown pre-mRNA to generate mRNA encoding a nicking endonuclease specific to the stem-loop structure. Transcription of the S and V regions, which contain palindromic sequences, leads to transient denaturation, forming the stem-loop structure that is cleaved by the AID-regulated endonuclease. Cleaved single-strand tails will be processed by error-prone DNA polymerase-mediated gap-filling or exonuclease-mediated resection. Mismatched bases will be corrected or fixed by mismatch repair enzymes. CSR ends are then ligated by the NHEJ system while SHM nicks are repaired by another ligation system.

参考文献

[1]  D. Durocher,et al.  Localization of the Catf1 transcription factor gene to mouse Chromosome 19 , 1995, Mammalian Genome.

[2]  T. Honjo,et al.  Variable deletion and duplication at recombination junction ends: Implication for staggered double-strand cleavage in class-switch recombination , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Honjo,et al.  A hallmark of active class switch recombination: Transcripts directed by I promoters on looped-out circular DNAs , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  T. Honjo,et al.  In situ class switching and differentiation to IgA-producing cells in the gut lamina propria , 2001, Nature.

[5]  T. Honjo,et al.  Quantitative Regulation of Class Switch Recombination by Switch Region Transcription , 2001, The Journal of experimental medicine.

[6]  Neal N. Iwakoshi,et al.  Plasma cell differentiation requires the transcription factor XBP-1 , 2001, Nature.

[7]  Gouri Nanjangud,et al.  Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas , 2001, Nature.

[8]  M. Flajnik,et al.  Decreased Frequency of Somatic Hypermutation and Impaired Affinity Maturation but Intact Germinal Center Formation in Mice Expressing Antisense RNA to DNA Polymerase ζ1 , 2001, The Journal of Immunology.

[9]  R. Zinkernagel,et al.  IgA production without μ or δ chain expression in developing B cells , 2001, Nature Immunology.

[10]  T. Honjo,et al.  Linking class-switch recombination with somatic hypermutation , 2001, Nature Reviews Molecular Cell Biology.

[11]  Toshiro Matsuda,et al.  Somatic mutation hotspots correlate with DNA polymerase η error spectrum , 2001, Nature Immunology.

[12]  M. Flajnik,et al.  The translesion DNA polymerase zeta plays a major role in Ig and bcl-6 somatic hypermutation. , 2001, Immunity.

[13]  Q. Kong,et al.  DNA breaks in hypermutating immunoglobulin genes: evidence for a break-and-repair pathway of somatic hypermutation. , 2001, Genetics.

[14]  P. Cramer,et al.  Structural Basis of Transcription: An RNA Polymerase II Elongation Complex at 3.3 Å Resolution , 2001, Science.

[15]  V. Gray-Schopfer,et al.  Increased Transcription Levels Induce Higher Mutation Rates in a Hypermutating Cell Line1 , 2001, The Journal of Immunology.

[16]  T. Honjo,et al.  Palindromic but not G-rich sequences are targets of class switch recombination. , 2001, International immunology.

[17]  H. Jacobs,et al.  Towards an understanding of somatic hypermutation. , 2001, Current opinion in immunology.

[18]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[19]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[20]  D. Cockayne,et al.  Signals That Initiate Somatic Hypermutation of B Cells In Vitro1 , 2001, The Journal of Immunology.

[21]  M. Neuberger,et al.  Somatic hypermutation of immunoglobulin κ transgenes: Association of mutability with demethylation , 2001, Immunology and cell biology.

[22]  F. Deist,et al.  CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Thomas B. Kepler,et al.  The Targeting of Somatic Hypermutation Closely Resembles That of Meiotic Mutation1 , 2001, The Journal of Immunology.

[24]  E. Selsing,et al.  The μ Switch Region Tandem Repeats Are Important, but Not Required, for Antibody Class Switch Recombination , 2001, The Journal of experimental medicine.

[25]  P. Gearhart,et al.  DNA polymerase η is an A-T mutator in somatic hypermutation of immunoglobulin variable genes , 2001, Nature Immunology.

[26]  V. Diehl,et al.  Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction , 2000, The Journal of experimental medicine.

[27]  A. Fischer,et al.  Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome. , 2000, Clinical immunology.

[28]  C. Hew,et al.  The rat ortholog of the presumptive flounder antifreeze enhancer-binding protein is a helicase domain-containing protein. , 2000, European journal of biochemistry.

[29]  K. Calame,et al.  BLIMP-1 mediates extinction of major histocompatibility class II transactivator expression in plasma cells , 2000, Nature Immunology.

[30]  M. Neuberger,et al.  Somatic Hypermutation in the Absence of DNA-Dependent Protein Kinase Catalytic Subunit (DNA-Pkcs) or Recombination-Activating Gene (Rag)1 Activity , 2000, The Journal of experimental medicine.

[31]  D. Schatz,et al.  Cell-cycle-regulated DNA double-strand breaks in somatic hypermutation of immunoglobulin genes , 2000, Nature.

[32]  Yaofeng Zhao,et al.  Mapping of the chicken immunoglobulin heavy‐chain constant region gene locus reveals an inverted α gene upstream of a condensed υ gene , 2000 .

[33]  K. Rajewsky,et al.  DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. , 2000, Immunity.

[34]  J. Pound,et al.  Signals sustaining human immunoglobulin V gene hypermutation in isolated germinal centre B cells , 2000, Immunology.

[35]  A. Fischer,et al.  Activation-Induced Cytidine Deaminase (AID) Deficiency Causes the Autosomal Recessive Form of the Hyper-IgM Syndrome (HIGM2) , 2000, Cell.

[36]  T. Honjo,et al.  Class Switch Recombination and Hypermutation Require Activation-Induced Cytidine Deaminase (AID), a Potential RNA Editing Enzyme , 2000, Cell.

[37]  M. Taniwaki,et al.  Isolation, tissue distribution, and chromosomal localization of the human activation-induced cytidine deaminase (AID) gene. , 2000, Genomics.

[38]  F. Alt,et al.  Transcription-induced Cleavage of Immunoglobulin Switch Regions by Nucleotide Excision Repair Nucleases in Vitro* , 2000, The Journal of Biological Chemistry.

[39]  L. Hammarström,et al.  An allotype‐associated polymorphism in the γ3 promoter determines the germ‐line γ3 transcriptional rate but does not influence switching and subsequent IgG3 production , 2000 .

[40]  T. Honjo,et al.  Increased Frequency of Surface IgA-Positive Plasma Cells in the Intestinal Lamina Propria and Decreased IgA Excretion in Hyper IgA (HIGA) Mice, a Murine Model of IgA Nephropathy with Hyperserum IgA1 , 2000, The Journal of Immunology.

[41]  N. Maizels,et al.  Transcriptional activation by LR1 at the Emu enhancer and switch region sites. , 2000, Nucleic acids research.

[42]  K. Kuma,et al.  Class switch recombination of the chicken IgH chain genes: implications for the primordial switch region repeats. , 2000, International immunology.

[43]  J. Schlessinger,et al.  Absence of marginal zone B cells in Pyk-2–deficient mice defines their role in the humoral response , 2000, Nature Immunology.

[44]  F. Buck,et al.  Purification and Molecular Cloning of a Novel Essential Component of the Apolipoprotein B mRNA Editing Enzyme-Complex* , 2000, The Journal of Biological Chemistry.

[45]  R. Zinkernagel,et al.  A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. , 2000, Science.

[46]  F. Hanaoka,et al.  Mechanisms of accurate translesion synthesis by human DNA polymerase η , 2000, The EMBO journal.

[47]  P. Lipsky,et al.  Targeting and selection of mutations in human Vλ rearrangements , 2000 .

[48]  E. Friedberg,et al.  The many faces of DNA polymerases: strategies for mutagenesis and for mutational avoidance. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Chikahide Masutani,et al.  Low fidelity DNA synthesis by human DNA polymerase-η , 2000, Nature.

[50]  J. Stavnezer,et al.  Evidence for Class-Specific Factors in Immunoglobulin Isotype Switching , 2000, The Journal of experimental medicine.

[51]  J. Stavnezer,et al.  Regulation of the promoter for human immunoglobulin γ3 germ‐line transcription and its interaction with the 3'α enhancer , 2000, European journal of immunology.

[52]  T. Honjo,et al.  Unique and unprecedented recombination mechanisms in class switching. , 2000, Current Opinion in Immunology.

[53]  Satya Prakash,et al.  Fidelity of Human DNA Polymerase η* , 2000, The Journal of Biological Chemistry.

[54]  N. Sherman,et al.  Molecular Cloning of Apobec-1 Complementation Factor, a Novel RNA-Binding Protein Involved in the Editing of Apolipoprotein B mRNA , 2000, Molecular and Cellular Biology.

[55]  R. Jessberger,et al.  Association of SWAP-70 with the B cell antigen receptor complex. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  W. Edelmann,et al.  Somatic Hypermutation in Muts Homologue (Msh)3-, Msh6-, and Msh3/Msh6-Deficient Mice Reveals a Role for the Msh2–Msh6 Heterodimer in Modulating the Base Substitution Pattern , 2000, The Journal of experimental medicine.

[57]  T. Grundström,et al.  Smad and AML Proteins Synergistically Confer Transforming Growth Factor β1 Responsiveness to Human Germ-line IgA Genes* , 2000, The Journal of Biological Chemistry.

[58]  P. Lipsky,et al.  Somatic hypermutation of VκJκ rearrangements: targeting of RGYW motifs on both DNA strands and preferential selection of mutated codons within RGYW motifs , 1999 .

[59]  C. Murre,et al.  E2A activity is induced during B‐cell activation to promote immunoglobulin class switch recombination , 1999, The EMBO journal.

[60]  F. Alt,et al.  The Ig heavy chain intronic enhancer core region is necessary and sufficient to promote efficient class switch recombination. , 1999, International immunology.

[61]  L. Hammarström,et al.  Targeting of human switch recombination breakpoints: implications for the mechanism of μ ‐ γ isotype switching , 1999 .

[62]  J. Stavnezer,et al.  Switch recombination in a transfected plasmid occurs preferentially in a B cell line that undergoes switch recombination of its chromosomal Ig heavy chain genes. , 1999, Journal of immunology.

[63]  R. Kucherlapati,et al.  Reduced Isotype Switching in Splenic B Cells from Mice Deficient in Mismatch Repair Enzymes , 1999, The Journal of experimental medicine.

[64]  U. Storb,et al.  Different Mismatch Repair Deficiencies All Have the Same Effects on Somatic Hypermutation , 1999, The Journal of experimental medicine.

[65]  T. Honjo,et al.  Specific Expression of Activation-induced Cytidine Deaminase (AID), a Novel Member of the RNA-editing Deaminase Family in Germinal Center B Cells* , 1999, The Journal of Biological Chemistry.

[66]  M. Neuberger,et al.  Deficiency in Msh2 affects the efficiency and local sequence specificity of immunoglobulin class‐switch recombination: parallels with somatic hypermutation , 1999, The EMBO journal.

[67]  R. Jessberger,et al.  Cellular, intracellular, and developmental expression patterns of murine SWAP‐70 , 1999, European journal of immunology.

[68]  L. Wyns,et al.  LOSS OF SPLICE CONSENSUS SIGNAL IS RESPONSIBLE FOR THE REMOVAL OF THE ENTIRE CH1 DOMAIN OF THE FUNCTIONAL CAMEL IGG2A HEAVY-CHAIN ANTIBODIES' , 1999 .

[69]  Ström,et al.  Characterization of CD40‐Dependent Immunoglobulin Class Switching , 1999, Scandinavian journal of immunology.

[70]  T. Serikawa,et al.  Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-κb-inducing kinase , 1999, Nature Genetics.

[71]  Andreas Radbruch,et al.  An extrachromosomal switch recombination substrate reveals kinetics and substrate requirements of switch recombination in primary murine B cells. , 1999, International immunology.

[72]  F. Alt,et al.  Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[73]  P. Gearhart,et al.  Hypermutation in Ig V genes from mice deficient in the MLH1 mismatch repair protein. , 1999, Journal of immunology.

[74]  P. Casali,et al.  Induction of Ig somatic hypermutation and class switching in a human monoclonal IgM+ IgD+ B cell line in vitro: definition of the requirements and modalities of hypermutation. , 1999, Journal of immunology.

[75]  S. Akira,et al.  IL-5 induces IgG1 isotype switch recombination in mouse CD38-activated sIgD-positive B lymphocytes. , 1999, Journal of immunology.

[76]  Q. Zhang,et al.  Smubp-2 represses the Epstein-Barr virus lytic switch promoter. , 1999, Virology.

[77]  F. Alt,et al.  Recombination and transcription of the endogenous Ig heavy chain locus is effected by the Ig heavy chain intronic enhancer core region in the absence of the matrix attachment regions. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[78]  Q. Kong,et al.  PMS2-deficiency diminishes hypermutation of a λ1 transgene in young but not older mice , 1999 .

[79]  T. Grundström,et al.  AML and Ets proteins regulate the Iα1 germ‐line promoter , 1999, European journal of immunology.

[80]  J. Willers,et al.  Apparent trans-chromosomal antibody class switch in mice bearing an Igh(a) mu-chain transgene on an Igh(b) genetic background. , 1999, Immunobiology.

[81]  T. Manser,et al.  Severe Attenuation of the B Cell Immune Response in Msh2-deficient Mice , 1999, The Journal of experimental medicine.

[82]  K. Roberts,et al.  Regulation of the germline immunoglobulin Cγ1 promoter by CD40 ligand and IL-4: dual role for tandemNF-κB binding sites , 1999 .

[83]  T. Honjo,et al.  Molecular mechanism of immunoglobulin class switch recombination. , 1999, Cold Spring Harbor symposia on quantitative biology.

[84]  J. Stavnezer,et al.  Iα exon-replacement mice synthesize a spliced HPRT–Cα transcript which may explain their ability to switch to IgA. Inhibition of switching to IgG in these mice , 1999 .

[85]  Andreas Radbruch,et al.  Processing of Switch Transcripts Is Required for Targeting of Antibody Class Switch Recombination , 1998, The Journal of experimental medicine.

[86]  T. Honjo,et al.  Target specificity of immunoglobulin class switch recombination is not determined by nucleotide sequences of S regions. , 1998, Immunity.

[87]  M. Neuberger,et al.  TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. , 1998, Immunity.

[88]  C. Mahaffey,et al.  Identification of the Mouse Neuromuscular Degeneration Gene and Mapping of a Second Site Suppressor Allele , 1998, Neuron.

[89]  P. Casali,et al.  CD40 Engagement Triggers Switching to IgA1 and IgA2 in Human B Cells Through Induction of Endogenous TGF-β: Evidence for TGF-β But Not IL-10-Dependent Direct Sμ→Sα and Sequential Sμ→Sγ, Sγ→Sα DNA Recombination , 1998, The Journal of Immunology.

[90]  F. Alt,et al.  An expressed neo(r) cassette provides required functions of the 1gamma2b exon for class switching. , 1998, International immunology.

[91]  N. Maizels,et al.  A Specific Isoform of hnRNP D Interacts with DNA in the LR1 Heterodimer: Canonical RNA Binding Motifs in a Sequence-specific Duplex DNA Binding Protein* , 1998, The Journal of Biological Chemistry.

[92]  F. Alt,et al.  Class Switching in B Cells Lacking 3′ Immunoglobulin Heavy Chain Enhancers , 1998, The Journal of experimental medicine.

[93]  N. Maizels,et al.  Localization of splenic B cells activated for switch recombination by in situ hybridization with Igamma1 switch transcript and Rad51 probes. , 1998, Journal of immunology.

[94]  P. Lipsky,et al.  Somatic hypermutation of human immunoglobulin heavy chain genes: targeting of RGYW motifs on both DNA strands , 1998, European journal of immunology.

[95]  L. Pasqualucci,et al.  BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[96]  M. Kingzette,et al.  Trans-chromosomal recombination within the Ig heavy chain switch region in B lymphocytes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[97]  Y. Yamaguchi-Iwai,et al.  Homologous recombination and non‐homologous end‐joining pathways of DNA double‐strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells , 1998, The EMBO journal.

[98]  J. Stavnezer,et al.  The Ability of CD40L, but Not Lipopolysaccharide, To Initiate Immunoglobulin Switching to Immunoglobulin G1 Is Explained by Differential Induction of NF-κB/Rel Proteins , 1998, Molecular and Cellular Biology.

[99]  U. Storb,et al.  A Hypermutable Insert in an Immunoglobulin Transgene Contains Hotspots of Somatic Mutation and Sequences Predicting Highly Stable Structures in the RNA Transcript , 1998, The Journal of experimental medicine.

[100]  C. Snapper,et al.  Efficient recombination of a switch substrate retrovector in CD40-activated B lymphocytes: implications for the control of CH gene switch recombination. , 1998, Journal of immunology.

[101]  F. Delbos,et al.  Probing immunoglobulin gene hypermutation with microsatellites suggests a nonreplicative short patch DNA synthesis process. , 1998, Immunity.

[102]  U. Storb,et al.  Somatic Hypermutation of an Artificial Test Substrate Within an Igκ Transgene , 1998, The Journal of Immunology.

[103]  R. Jessberger,et al.  A B-cell-specific DNA Recombination Complex* , 1998, The Journal of Biological Chemistry.

[104]  K. Rajewsky,et al.  Somatic hypermutation in the heavy chain locus correlates with transcription. , 1998, Immunity.

[105]  F. Delbos,et al.  Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process. , 1998, Immunity.

[106]  C. Milstein,et al.  Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. , 1998, Immunity.

[107]  P. Thompson,et al.  STAT6 is required for IL-4-induced germline Ig gene transcription and switch recombination. , 1998, Journal of immunology.

[108]  F. Alt,et al.  Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching , 1998, The Journal of experimental medicine.

[109]  U. Storb,et al.  Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. , 1998, Science.

[110]  T. Kunkel,et al.  Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[111]  F. Alt,et al.  Reevaluation of 3'Ekappa function in stage- and lineage-specific rearrangement and somatic hypermutation. , 1998, Immunity.

[112]  F. Alt,et al.  Deletion of the IgH intronic enhancer and associated matrix-attachment regions decreases, but does not abolish, class switching at the mu locus. , 1998, International immunology.

[113]  N. de Wind,et al.  Hypermutation of Immunoglobulin Genes in Memory B Cells of DNA Repair–deficient Mice , 1998, The Journal of experimental medicine.

[114]  R. Tarone,et al.  Increased Hypermutation at G and C Nucleotides in Immunoglobulin Variable Genes from Mice Deficient in the MSH2 Mismatch Repair Protein , 1998, The Journal of experimental medicine.

[115]  N. Motoyama,et al.  Affinity maturation in Lyn kinase-deficient mice with defective germinal center formation. , 1998, Journal of immunology.

[116]  Heikyung Suh,et al.  Ku80 is required for immunoglobulin isotype switching , 1998, The EMBO journal.

[117]  C. Snapper,et al.  Multiple Hemopoietic Defects and Lymphoid Hyperplasia in Mice Lacking the Transcriptional Activation Domain of the c-Rel Protein , 1998, The Journal of experimental medicine.

[118]  K. Marcu,et al.  Stimulation of murine B lymphocytes induces a DNA exonuclease whose activity on switch-mu DNA is specifically inhibited by other germ-line switch region RNAs. , 1998, Journal of immunology.

[119]  U. Storb,et al.  Progress in understanding the mechanism and consequences of somatic hypermutation , 1998, Immunological reviews.

[120]  J. Hackett,et al.  Cis‐acting sequences that affect somatic hypermutation of Ig genes , 1998, Immunological reviews.

[121]  N. Chitkara,et al.  The Ig mutator is dependent on the presence, position, and orientation of the large intron enhancer. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[122]  U. Klein,et al.  Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[123]  M. Wabl,et al.  Mismatch repair co-opted by hypermutation. , 1998, Science.

[124]  Tasuku Honjo,et al.  Frequent but biased class switch recombination in the Sμ flanking regions , 1998, Current Biology.

[125]  A. Leonardi,et al.  Mice Deficient in Nuclear Factor (NF)-κB/p52 Present with Defects in Humoral Responses, Germinal Center Reactions, and Splenic Microarchitecture , 1998, The Journal of experimental medicine.

[126]  C. Snapper,et al.  Nuclear Factor (NF)-κB2 (p100/p52) Is Required for Normal Splenic Microarchitecture and B Cell–mediated Immune Responses , 1998, The Journal of experimental medicine.

[127]  B. Barnhart,et al.  CD40 ligand exerts differential effects on the expression of I gamma transcripts in subclones of an IgM+ human B cell lymphoma line. , 1998, Journal of immunology.

[128]  Akira Shinohara,et al.  Rad51‐deficient vertebrate cells accumulate chromosomal breaks prior to cell death , 1998, The EMBO journal.

[129]  Virginia Pascual,et al.  Somatic Hypermutation Introduces Insertions and Deletions into Immunoglobulin V Genes , 1998, The Journal of experimental medicine.

[130]  M. Neuberger,et al.  Multiple sequences from downstream of the Jκ cluster can combine to recruit somatic hypermutation to a heterologous, upstream mutation domain , 1998, European journal of immunology.

[131]  L. Herzenberg,et al.  Presence of Germline and Full-Length IgA RNA Transcripts Among Peritoneal B-1 Cells , 1998, Developmental immunology.

[132]  M. Wabl,et al.  Critical test of hot spot motifs for immunoglobulin hypermutation , 1997, European journal of immunology.

[133]  C. Milstein,et al.  The 5′ hypermutation boundary of x chains is independent of local and neighbouring sequences and related to the distance from the initiation of transcription , 1997, European journal of immunology.

[134]  N. Maizels,et al.  Nuclear Rad51 foci induced by DNA damage are distinct from Rad51 foci associated with B cell activation and recombination. , 1997, Experimental cell research.

[135]  A. Kenter,et al.  Ig Sgamma3 DNA-specifc double strand breaks are induced in mitogen-activated B cells and are implicated in switch recombination. , 1997, Journal of immunology.

[136]  L. Du Pasquier,et al.  Microsites for immunoglobulin switch recombination breakpoints from Xenopus to mammals , 1997, European journal of immunology.

[137]  A. Stütz,et al.  Cooperation of binding sites for STAT6 and NF kappa B/rel in the IL-4-induced up-regulation of the human IgE germline promoter. , 1997, Journal of immunology.

[138]  C. Snapper,et al.  B cells genetically deficient in the c-Rel transactivation domain have selective defects in germline CH transcription and Ig class switching. , 1997, Journal of immunology.

[139]  J. Kearney,et al.  Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses , 1997, European journal of immunology.

[140]  M. Lefranc,et al.  B Lymphocytes of Xeroderma Pigmentosum or Cockayne Syndrome Patients with Inherited Defects in Nucleotide Excision Repair Are Fully Capable of Somatic Hypermutation of Immunoglobulin Genes , 1997, The Journal of experimental medicine.

[141]  A. Shanmugam,et al.  Analysis of immunoglobulin Sgamma3 recombination breakpoints by PCR: implications for the mechanism of isotype switching. , 1997, Nucleic acids research.

[142]  A. Kenter,et al.  Ig S gamma-specific DNA binding protein SNAP is related to the helix-loop-helix transcription factor E47. , 1997, International immunology.

[143]  K. Marcu,et al.  Antibody class switch recombinase activity is B cell stage specific and functions stochastically in the absence of 'targeted accessibility' control. , 1997, International immunology.

[144]  C. Milstein,et al.  Cells strongly expressing Igκ transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers , 1997, The EMBO journal.

[145]  D. Chaplin,et al.  Lymphotoxin-α (LTα) Supports Development of Splenic Follicular Structure That Is Required for IgG Responses , 1997, The Journal of experimental medicine.

[146]  J. Stavnezer,et al.  CD40 cross-linking induces Ig epsilon germline transcripts in B cells via activation of NF-kappaB: synergy with IL-4 induction. , 1997, Journal of immunology.

[147]  D. Cheo,et al.  The inactivation of the XP-C gene does not affect somatic hypermutation or class switch recombination of immunoglobulin genes. , 1997, Molecular immunology.

[148]  J. Hoeijmakers,et al.  Disruption of Mouse RAD54 Reduces Ionizing Radiation Resistance and Homologous Recombination , 1997, Cell.

[149]  N. Maizels,et al.  Nucleolin is one component of the B cell-specific transcription factor and switch region binding protein, LR1. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[150]  P. Gearhart,et al.  Insertion of 2 kb of bacteriophage DNA between an immunoglobulin promoter and leader exon stops somatic hypermutation in a kappa transgene. , 1997, Molecular immunology.

[151]  A. Sher,et al.  Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions. , 1997, Immunity.

[152]  R. Brezinschek,et al.  Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. , 1997, Journal of immunology.

[153]  C. Snapper,et al.  The immunoglobulin class switch: beyond "accessibility". , 1997, Immunity.

[154]  B. Ryffel,et al.  Lack of type 2 T cell-independent B cell responses and defect in isotype switching in TNF-lymphotoxin alpha-deficient mice. , 1997, Journal of immunology.

[155]  H. Tokuyama,et al.  Retinoic Acid Induces the Expression of Germ-Line Cα Transcript Mainly by a TGF-β-Independent Mechanism☆ , 1997 .

[156]  K. Kajiwara,et al.  Possible Role of Nuclear Factor-κB Activity in Germline Cϵ Transcription in a Human Burkitt Lymphoma B Cell Line , 1997 .

[157]  R. Aguilera,et al.  Purification and characterization of the immunoglobulin switch sequence-specific endonuclease (Endo-SR) from bovine spleen. , 1997, Molecular immunology.

[158]  N. Maizels,et al.  Developmental specificity of immunoglobulin heavy chain switch region recombination activities. , 1997, Molecular immunology.

[159]  T. Mak,et al.  Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function , 1997, Science.

[160]  T. Manser,et al.  The Transcriptional Promoter Regulates Hypermutation of the Antibody Heavy Chain Locus , 1997, The Journal of experimental medicine.

[161]  Jishan Sun,et al.  Sequence analysis of pig switch μ, Cμ, and Cμm , 1997, Immunogenetics.

[162]  R. Coffman,et al.  CD40 signaling induces interleukin‐4‐independent IgE switching in vivo , 1996, European journal of immunology.

[163]  A. Saxon,et al.  Direct evidence that gamma 1 and gamma 3 switching in human B cells is interleukin-10 dependent. , 1996, Molecular immunology.

[164]  C. Milstein,et al.  Modifying the sequence of an immunoglobulin V-gene alters the resulting pattern of hypermutation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[165]  A. Rolink,et al.  The SCID but Not the RAG-2 Gene Product Is Required for Sμ–Sε Heavy Chain Class Switching , 1996 .

[166]  G. Kollias,et al.  Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response , 1996, The Journal of experimental medicine.

[167]  D. Ward,et al.  Rad51 expression and localization in B cells carrying out class switch recombination. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[168]  A. Duschl,et al.  The Human IgE Germline Promoter is Regulated By Interleukin‐4, Interleukin‐13, Interferon‐α and Interferon‐γ Via an Interferon‐γ‐Activated Site and Its Flanking Regions , 1996 .

[169]  H. Arakawa,et al.  Chicken immunoglobulin μ-chain gene: germline organization and tandem repeats characteristic of class switch recombination , 1996 .

[170]  J. Stavnezer,et al.  Activation of NF-kappaB/Rel by CD40 engagement induces the mouse germ line immunoglobulin Cgamma1 promoter , 1996, Molecular and cellular biology.

[171]  P. Lipsky,et al.  A CD30 responsive element in the germline ϵ promoter that is distinct from and inhibitory to the CD40 response element , 1996 .

[172]  A. Goldfarb,et al.  Involvement of the E2A basic helix-loop-helix protein in immunoglobulin heavy chain class switching. , 1996, Molecular immunology.

[173]  R. Geha,et al.  Affinity maturation without germinal centres in lymphotoxin-α-deficient mice , 1996, Nature.

[174]  T. Honjo,et al.  Defects of somatic hypermutation and class switching in alymphoplasia (aly) mutant mice. , 1996, International immunology.

[175]  K. Rajewsky.  Clonal selection and learning in the antibody system , 1996, Nature.

[176]  M. Lieber,et al.  Asymmetric mutation around the recombination break point of immunoglobulin class switch sequences on extrachromosomal substrates. , 1996, Nucleic acids research.

[177]  D. R. Taylor,et al.  Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation , 1996, The Journal of experimental medicine.

[178]  B. Ryffel,et al.  Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling , 1996, The Journal of experimental medicine.

[179]  C. Turck,et al.  Translatable immunoglobulin germ‐line transcript , 1996, European journal of immunology.

[180]  J. Banchereau,et al.  Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. , 1996, Immunity.

[181]  T. Honjo,et al.  High frequency class switching of an IgM+ B lymphoma clone CH12F3 to IgA+ cells. , 1996, International immunology.

[182]  R. Aguilera,et al.  Characterization of an endonuclease activity which preferentially cleaves the G-rich immunoglobulin switch repeat sequences. , 1996, Molecular immunology.

[183]  F. Kroese,et al.  Monoclonal immunoglobulin A derived from peritoneal B cells is encoded by both germ line and somatically mutated VH genes and is reactive with commensal bacteria , 1996, Infection and immunity.

[184]  A. Bradley,et al.  IgA class switch in I alpha exon-deficient mice. Role of germline transcription in class switch recombination. , 1996, The Journal of clinical investigation.

[185]  R. Zinkernagel,et al.  Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-α double-deficient mice , 1996 .

[186]  U. Storb,et al.  Somatic hypermutation of immunoglobulin genes is linked to transcription initiation. , 1996, Immunity.

[187]  S. Knuutila,et al.  A human follicular lymphoma B cell line hypermutates its functional immunoglobulin genes in vitro , 1995, European journal of immunology.

[188]  Christina A. Cuomo,et al.  Cleavage at a V(D)J recombination signal requires only RAG1 and RAG2 proteins and occurs in two steps , 1995, Cell.

[189]  C. Milstein,et al.  Targeting of non-lg sequences in place of the V segment by somatic hyper mutation , 1995, Nature.

[190]  J. Stavnezer,et al.  Cell cycle regulation of immunoglobulin class switch recombination and germ‐line transcription: potential role of Ets family members , 1995, European journal of immunology.

[191]  M. Lieber,et al.  Strand specificity in the transcriptional targeting of recombination at immunoglobulin switch sequences. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[192]  R. Aguilera,et al.  The murine nucleolin protein is an inducible DNA and ATP binding protein which is readily detected in nuclear extracts of lipopolysaccharide-treated splenocytes. , 1995, Experimental cell research.

[193]  Andreas Radbruch,et al.  Switch transcripts in immunoglobulin class switching. , 1995, Science.

[194]  T. Honjo,et al.  Regulation of class switch recombination of the immunoglobulin heavy chain genes , 1995 .

[195]  M. Lieber,et al.  RNA:DNA complex formation upon transcription of immunoglobulin switch regions: implications for the mechanism and regulation of class switch recombination. , 1995, Nucleic acids research.

[196]  F. Kroese,et al.  A dual origin for IgA plasma cells in the murine small intestine. , 1995, Advances in experimental medicine and biology.

[197]  R. Kumar,et al.  Extrachromosomal eukaryotic DNA substrates for switch recombination: analysis of isotype and cell specificity. , 1994, DNA and cell biology.

[198]  R. Flavell,et al.  Mice deficient for the CD40 ligand. , 1994, Immunity.

[199]  J. D. Capra,et al.  Analysis of somatic mutation in five B cell subsets of human tonsil , 1994, The Journal of experimental medicine.

[200]  F. Alt,et al.  A class switch control region at the 3′ end of the immunoglobulin heavy chain locus , 1994, Cell.

[201]  N. Yoshida,et al.  The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. , 1994, Immunity.

[202]  C. Milstein,et al.  Elements regulating somatic hypermutation of an immunoglobulin κ gene: Critical role for the intron enhancer/matrix attachment region , 1994, Cell.

[203]  H. Cedar,et al.  B cell-specific demethylation: A novel role for the intronic κ chain enhancer sequence , 1994, Cell.

[204]  F. Alt,et al.  S region transcription per se promotes basal IgE class switch recombination but additional factors regulate the efficiency of the process. , 1994, The EMBO journal.

[205]  S. Ikehara,et al.  A new mutation, aly, that induces a generalized lack of lymph nodes accompanied by immunodeficiency in mice , 1994, European journal of immunology.

[206]  G. Merkulov,et al.  Switch recombination breakpoints occur at nonrandom positions in the Sγ tandem repeat , 1993 .

[207]  R. Callard,et al.  CD40 ligand and its role in X-linked hyper-IgM syndrome. , 1993, Immunology today.

[208]  V. Stewart,et al.  A selective defect in IgG2b switching as a result of targeted mutation of the I gamma 2b promoter and exon. , 1993, The EMBO journal.

[209]  K. Rajewsky,et al.  Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting , 1993, Cell.

[210]  G. Hertz,et al.  Corrigenda DNA sequences at immunoglobulin switch region recombination sites , 1993 .

[211]  A Shimizu,et al.  Isolation of cDNA encoding a binding protein specific to 5'-phosphorylated single-stranded DNA with G-rich sequences. , 1993, Nucleic acids research.

[212]  F. Alt,et al.  Replacement of germ-line epsilon promoter by gene targeting alters control of immunoglobulin heavy chain class switching. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[213]  C. Milstein,et al.  Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[214]  H. Arakawa,et al.  The complete murine immunoglobulin class switch region of the alpha heavy chain gene-hierarchic repetitive structure and recombination breakpoints. , 1993, The Journal of biological chemistry.

[215]  K. Rajewsky,et al.  Shutdown of class switch recombination by deletion of a switch region control element , 1993, Science.

[216]  G. Hertz,et al.  DNA sequences at immunoglobulin switch region recombination sites. , 1993, Nucleic acids research.

[217]  D. Loh,et al.  Mutations of the chloramphenicol acetyl transferase transgene driven by the immunoglobulin promoter and intron enhancer. , 1993, International immunology.

[218]  N A Kolchanov,et al.  Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequences on mutagenesis. , 1992, Biochimica et biophysica acta.

[219]  K. Marcu,et al.  Properties of B cell stage specific and ubiquitous nuclear factors binding to immunoglobulin heavy chain gene switch regions. , 1992, International immunology.

[220]  G. Merkulov,et al.  Switch recombination breakpoints are strictly correlated with DNA recognition motifs for immunoglobulin S gamma 3 DNA-binding proteins , 1992, The Journal of experimental medicine.

[221]  N. Maizels,et al.  Transcriptional regulatory elements stimulate recombination in extrachromosomal substrates carrying immunoglobulin switch-region sequences. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[222]  M. Muller,et al.  Eukaryotic topoisomerase II cleavage of parallel stranded DNA tetraplexes. , 1992, Nucleic acids research.

[223]  C. Berek,et al.  Maturation of the immune response in germinal centers , 1991, Cell.

[224]  Klaus Rajewsky,et al.  Intraclonal generation of antibody mutants in germinal centres , 1991, Nature.

[225]  N. Maizels,et al.  LR1, a lipopolysaccharide-responsive factor with binding sites in the immunoglobulin switch regions and heavy-chain enhancer. , 1991, Genes & development.

[226]  A. Kenter,et al.  High expression of a 3'----5' exonuclease activity is specific to B lymphocytes , 1991, Molecular and cellular biology.

[227]  L. Elenich,et al.  Nuclear protein binding to octamer motifs in the immunoglobulin gamma 1 switch region. , 1991, International immunology.

[228]  T. Honjo,et al.  The membrane exons of the pseudo-γ-chain gene of the human immunoglobulin are apparently functional and highly homologous to those of the γ1 gene , 1991 .

[229]  P. Gearhart,et al.  Boundaries of somatic mutation in rearranged immunoglobulin genes: 5' boundary is near the promoter, and 3' boundary is approximately 1 kb from V(D)J gene , 1990, The Journal of experimental medicine.

[230]  J. Griffin,et al.  Induction of RNA-stabilized DMA conformers by transcription of an immunoglobulin switch region , 1990, Nature.

[231]  H. Sakano,et al.  Switch circular DNA formed in cytokine-treated mouse splenocytes: Evidence for intramolecular DNA deletion in immunoglobulin class switching , 1990, Cell.

[232]  T. Honjo,et al.  Circular DNA is excised by immunoglobulin class switch recombination , 1990, Cell.

[233]  M. Wabl,et al.  Circular DNA is a product of the immunoglobulin class switch rearrangement , 1990, Nature.

[234]  J. Stavnezer,et al.  Structure of germ line immunoglobulin alpha heavy-chain RNA and its location on polysomes , 1990, Molecular and cellular biology.

[235]  J. Stavnezer,et al.  A B-cell-specific nuclear protein that binds to DNA sites 5' to immunoglobulin S alpha tandem repeats is regulated during differentiation , 1989, Molecular and cellular biology.

[236]  K. Marcu,et al.  Molecular requirements for immunoglobulin heavy chain constant region gene switch-recombination revealed with switch-substrate retroviruses. , 1989, International immunology.

[237]  J. Stavnezer,et al.  Mutations, duplication, and deletion of recombined switch regions suggest a role for DNA replication in the immunoglobulin heavy-chain switch , 1989, Molecular and cellular biology.

[238]  Y. Kurosawa,et al.  Nucleotide sequence of Suncus murinus immunoglobulin μ gene and comparison with mouse and human μ genes , 1989, FEBS letters.

[239]  E. Butcher,et al.  A major peritoneal reservoir of precursors for intestinal IgA plasma cells. , 1989, Immunological investigations.

[240]  W. Gilbert,et al.  Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis , 1988, Nature.

[241]  R. Becker,et al.  Isolation of genes encoding bovine IgM, IgG, IgA and IgE chains. , 1987, Veterinary immunology and immunopathology.

[242]  V. V. Solovyov,et al.  Pecularities of immunoglobulin gene structures as a basis for somatic mutation emergence , 1987, FEBS letters.

[243]  Klaus Rajewsky,et al.  Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses , 1987, Cell.

[244]  F. Alt,et al.  Immunoglobulin heavy chain switch region recombination within a retroviral vector in murine pre‐B cells. , 1987, The EMBO journal.

[245]  F. Alt,et al.  Secondary genomic rearrangement events in pre‐B cells: VHDJH replacement by a LINE‐1 sequence and directed class switching. , 1986, The EMBO journal.

[246]  S. Sirlin,et al.  Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching. , 1986, The EMBO journal.

[247]  S. Latt,et al.  A novel alteration in the structure of an activated c-myc gene in a variant t(2;8) burkitt lymphoma , 1984, Cell.

[248]  S. Rudikoff,et al.  Somatic diversification of immunoglobulins. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[249]  T. Rabbitts,et al.  Transcription enhancer identified near the human Cμ immunoglobulin heavy chain gene is unavailable to the translocated c-myc gene in a Burkitt lymphoma , 1983, Nature.

[250]  T. Honjo,et al.  Nucleotide sequences of switch regions of immunoglobulin C epsilon and C gamma genes and their comparison. , 1982, The Journal of biological chemistry.

[251]  T. Honjo,et al.  Structure of human immunoglobulin gamma genes: implications for evolution of a gene family , 1982, Cell.

[252]  T. Honjo,et al.  Organization of the constant-region gene family of the mouse immunoglobulin heavy chain , 1982, Cell.

[253]  T. Honjo,et al.  Switch region of immunoglobulin Cμ gene is composed of simple tandem repetitive sequences , 1981, Nature.

[254]  T. Miyata,et al.  Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes , 1981, Cell.

[255]  T. Honjo,et al.  Cloning of human immunoglobulin mu gene and comparison with mouse mu gene. , 1980, Nucleic acids research.

[256]  H. Bilofsky,et al.  Some sequence similarities among cloned mouse DNA segments that code for lambda and kappa light chains of immunoglobulins. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[257]  S. Brenner,et al.  Origin of Antibody Variation , 1966, Nature.

引用
High levels of activation‐induced cytidine deaminase expression in adult T‐cell leukaemia/lymphoma
British Journal of Dermatology
2011
The Dynamics of Germinal Centre Selection as Measured by Graph-Theoretical Analysis of Mutational Lineage Trees
Developmental immunology
2002
Translocation t(11;14) in multiple myeloma: Analysis of translocation breakpoints on der(11) and der(14) chromosomes suggests complex molecular mechanisms of recombination
Genes, Chromosomes and Cancer
2004
Role of recombination activating genes in the generation of antigen receptor diversity and beyond
Immunology
2012
HIV infection: first battle decides the war.
Trends in immunology
2006
Biochemical Analysis of Hypermutational Targeting by Wild Type and Mutant Activation-induced Cytidine Deaminase*
Journal of Biological Chemistry
2004
Sequence-specific recruitment of transcriptional co-repressor Cabin1 by myocyte enhancer factor-2
Nature
2003
RNA editing by mammalian ADARs.
Advances in genetics
2011
Immune system learning and memory quantified by graphical analysis of B-lymphocyte phylogenetic trees.
Bio Systems
2004
Non-B DNA Conformations, Genomic Rearrangements, and Human Disease*
Journal of Biological Chemistry
2004
Over‐expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B‐cell lymphoma
Pathology international (Print)
2013
BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma.
Blood
2005
B-cell lymphoma: suppressing a tumor suppressor
Nature Medicine
2005
HIV-1 Envelope Triggers Polyclonal Ig Class Switch Recombination through a CD40-Independent Mechanism Involving BAFF and C-Type Lectin Receptors1
The Journal of Immunology
2006
Checkpoints in memory B‐cell evolution
Immunological reviews
2006
Germinal center selection and the development of memory B and plasma cells
Immunological reviews
2012
From T‐cell activation signals to signaling control of anti‐cancer immunity
Immunological reviews
2007
Somatic Hypermutation of Immunoglobulin Genes Merging Mechanisms for Genetic Diversity
Cell
2002
Activation-induced Deaminase (AID)-directed Hypermutation in the Immunoglobulin Sμ Region
The Journal of Experimental Medicine
2002
APE1 is dispensable for S-region cleavage but required for its repair in class switch recombination
Proceedings of the National Academy of Sciences
2014