E3-ubiquitin ligase Nedd4 determines the fate of AID-associated RNA polymerase II in B cells

During B-lymphocyte class switch recombination, mutagenesis of the immunoglobulin (Ig) locus requires RNA polII-dependent targeting of the DNA mutator AID, yet the mechanism is unknown. Sun et al. now show that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII at Ig switch regions. Loss of Nedd4 activity leads to RNA exosome substrate accumulation at AID target genes. This study links noncoding RNA processing following RNA polII pausing with AID regulation during class switch recombination.

[1]  L. Staudt,et al.  Identification of Early Replicating Fragile Sites that Contribute to Genome Instability , 2013, Cell.

[2]  F. Papavasiliou,et al.  Solubility-based genetic screen identifies RING finger protein 126 as an E3 ligase for activation-induced cytidine deaminase , 2012, Proceedings of the National Academy of Sciences.

[3]  S. Grewal,et al.  RNAi triggered by specialized machinery silences developmental genes and retrotransposons , 2012, Nature.

[4]  A. Kenter AID targeting is dependent on RNA polymerase II pausing. , 2012, Seminars in immunology.

[5]  H. Marusawa,et al.  Inflammation‐mediated genomic instability: roles of activation‐induced cytidine deaminase in carcinogenesis , 2012, Cancer science.

[6]  P. Cramer,et al.  A Movie of RNA Polymerase II Transcription , 2012, Cell.

[7]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[8]  Margaret S. Ebert,et al.  Roles for MicroRNAs in Conferring Robustness to Biological Processes , 2012, Cell.

[9]  S. Grewal,et al.  Different means, same end-heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast. , 2012, Current opinion in genetics & development.

[10]  Yong-tang Zheng,et al.  Zinc-finger antiviral protein inhibits HIV-1 infection by selectively targeting multiply spliced viral mRNAs for degradation , 2011, Proceedings of the National Academy of Sciences.

[11]  J. Stavnezer Complex regulation and function of activation-induced cytidine deaminase. , 2011, Trends in immunology.

[12]  F. Alt,et al.  The RNA Exosome Targets the AID Cytidine Deaminase to Both Strands of Transcribed Duplex DNA Substrates , 2011, Cell.

[13]  Vasco M. Barreto,et al.  Activation-Induced Cytidine Deaminase Targets DNA at Sites of RNA Polymerase II Stalling by Interaction with Spt5 , 2010, Cell.

[14]  G. Giglia-Mari,et al.  A Ubiquitin-Binding Domain in Cockayne Syndrome B Required for Transcription-Coupled Nucleotide Excision Repair , 2010, Molecular cell.

[15]  J. Svejstrup The interface between transcription and mechanisms maintaining genome integrity. , 2010, Trends in biochemical sciences.

[16]  Robert C Piper,et al.  Insights into ubiquitin transfer cascades from a structure of a UbcH5B approximately ubiquitin-HECT(NEDD4L) complex. , 2009, Molecular cell.

[17]  R. Conaway,et al.  Distinct ubiquitin ligases act sequentially for RNA polymerase II polyubiquitylation , 2009, Proceedings of the National Academy of Sciences.

[18]  Patricia Richard,et al.  Transcription termination by nuclear RNA polymerases. , 2009, Genes & development.

[19]  D. Rotin,et al.  Physiological functions of the HECT family of ubiquitin ligases , 2009, Nature Reviews Molecular Cell Biology.

[20]  A. Khamlichi,et al.  Immunoglobulin switch μ sequence causes RNA polymerase II accumulation and reduces dA hypermutation , 2009, The Journal of experimental medicine.

[21]  T. Jensen,et al.  Origins and activities of the eukaryotic exosome , 2009, Journal of Cell Science.

[22]  S. Salzberg,et al.  TopHat: discovering splice junctions with RNA-Seq , 2009, Bioinform..

[23]  Michael F. Lin,et al.  Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals , 2009, Nature.

[24]  Gene W. Yeo,et al.  Divergent Transcription from Active Promoters , 2008, Science.

[25]  P. Marrack,et al.  Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells , 2008, Nature Immunology.

[26]  Aaron Ciechanover,et al.  The HECT family of E3 ubiquitin ligases: multiple players in cancer development. , 2008, Cancer cell.

[27]  J. Weill,et al.  Proteasomal degradation restricts the nuclear lifespan of AID , 2008 .

[28]  P. Cramer,et al.  Structure of eukaryotic RNA polymerases. , 2008, Annual review of biophysics.

[29]  D. Schatz,et al.  Two levels of protection for the B cell genome during somatic hypermutation , 2008, Nature.

[30]  J. Svejstrup,et al.  Damage-induced ubiquitylation of human RNA polymerase II by the ubiquitin ligase Nedd4, but not Cockayne syndrome proteins or BRCA1. , 2007, Molecular cell.

[31]  P. V. D. van den Berk,et al.  A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification , 2007, The Journal of experimental medicine.

[32]  Steven P. Gygi,et al.  RNAi-Dependent and -Independent RNA Turnover Mechanisms Contribute to Heterochromatic Gene Silencing , 2007, Cell.

[33]  Takeshi Azuma,et al.  Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium , 2007, Nature Medicine.

[34]  Terence R. Strick,et al.  Abortive Initiation and Productive Initiation by RNA Polymerase Involve DNA Scrunching , 2006, Science.

[35]  John T. Lis,et al.  Breaking barriers to transcription elongation , 2006, Nature Reviews Molecular Cell Biology.

[36]  J. Manley,et al.  Cotranscriptional processes and their influence on genome stability. , 2006, Genes & development.

[37]  David Tollervey,et al.  RNA-quality control by the exosome , 2006, Nature Reviews Molecular Cell Biology.

[38]  F. Papavasiliou,et al.  The Transcription Elongation Complex Directs Activation-Induced Cytidine Deaminase-Mediated DNA Deamination , 2006, Molecular and Cellular Biology.

[39]  F. Alt,et al.  AID in somatic hypermutation and class switch recombination. , 2006, Current opinion in immunology.

[40]  Michel C. Nussenzweig,et al.  Role of genomic instability and p53 in AID-induced c-myc–Igh translocations , 2006, Nature.

[41]  A. Kenter,et al.  AID-dependent histone acetylation is detected in immunoglobulin S regions , 2006, The Journal of experimental medicine.

[42]  Michael M. Murphy,et al.  H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. , 2006, Molecular cell.

[43]  B. Séraphin,et al.  Cryptic Pol II Transcripts Are Degraded by a Nuclear Quality Control Pathway Involving a New Poly(A) Polymerase , 2005, Cell.

[44]  M. Neuberger,et al.  Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. , 2005, Molecular biology and evolution.

[45]  E. Decroly,et al.  APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles. , 2005, Journal of molecular biology.

[46]  D. Schatz,et al.  Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc , 2004, Nature Immunology.

[47]  U. Storb,et al.  Activation-induced cytidine deaminase (AID) can target both DNA strands when the DNA is supercoiled. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[48]  F. Alt,et al.  Transcription-targeted DNA deamination by the AID antibody diversification enzyme , 2003, Nature.

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

[50]  P. Mitchell,et al.  Functions of the exosome in rRNA, snoRNA and snRNA synthesis , 1999, The EMBO journal.

[51]  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.

[52]  F. Alt,et al.  Multiple immunoglobulin heavy-chain gene transcripts in Abelson murine leukemia virus-transformed lymphoid cell lines , 1982, Molecular and cellular biology.

[53]  Uttiya Basu,et al.  Regulation of AID, the B-cell genome mutator. , 2013, Genes & development.

[54]  M. Nussenzweig,et al.  AID targeting in antibody diversity. , 2011, Advances in immunology.

[55]  M. Nussenzweig,et al.  Deep-sequencing identification of the genomic targets of the cytidine deaminase AID and its cofactor RPA in B lymphocytes , 2011, Nature Immunology.

[56]  L. Pasqualucci,et al.  AID is required for germinal center–derived lymphomagenesis , 2008, Nature Genetics.

[57]  Mikkel H. Schierup,et al.  RNA Exosome Depletion Reveals Transcription Upstream of Active Human Promoters , 2008, Science.

[58]  F. Alt,et al.  Evolution of the immunoglobulin heavy chain class switch recombination mechanism. , 2007, Advances in immunology.

[59]  Vasco M. Barreto,et al.  The role of activation-induced deaminase in antibody diversification and chromosome translocations. , 2007, Advances in immunology.

[60]  Quansheng Liu,et al.  Reconstitution, Activities, and Structure of the Eukaryotic RNA Exosome , 2007, Cell.

[61]  D. Schatz,et al.  V(D)J recombination: molecular biology and regulation. , 1992, Annual review of immunology.