DNA methylation, methyltransferases, and cancer

The field of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new findings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects.

[1]  J. Herman,et al.  Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia. , 1998, Cancer research.

[2]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[3]  J. Herman,et al.  Epigenetic inactivation of LKB1 in primary tumors associated with the Peutz-Jeghers syndrome , 2000, Oncogene.

[4]  Peter L. Jones,et al.  DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters , 2000, Nature Genetics.

[5]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[6]  E. Ballestar,et al.  Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation , 1999, Nature Genetics.

[7]  N. Bérubé,et al.  Cell cycle-dependent phosphorylation of the ATRX protein correlates with changes in nuclear matrix and chromatin association. , 2000, Human molecular genetics.

[8]  J. Herman,et al.  Inactivation of glutathione S-transferase P1 gene by promoter hypermethylation in human neoplasia. , 1998, Cancer research.

[9]  R. Löwer,et al.  DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas , 1999, British Journal of Cancer.

[10]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.

[11]  B. Stillman,et al.  Chromatin Assembly Coupled to DNA Repair: A New Role for Chromatin Assembly Factor I , 1996, Cell.

[12]  V. Colot,et al.  Eukaryotic DNA methylation as an evolutionary device , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  Bruce Stillman,et al.  The p150 and p60 subunits of chromatin assemblyfactor I: A molecular link between newly synthesized histories and DNA replication , 1995, Cell.

[14]  R. Jaenisch,et al.  Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila , 1999, Nature Genetics.

[15]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Paul Tempst,et al.  MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex , 1999, Nature Genetics.

[17]  A. Bird,et al.  Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Garabedian,et al.  Differential regulation of glucocorticoid receptor transcriptional activation via AF‐1‐associated proteins , 1999, The EMBO journal.

[19]  G. Morin,et al.  Functional requirement of p23 and Hsp90 in telomerase complexes. , 1999, Genes & development.

[20]  Asad Umar,et al.  Requirement for PCNA in DNA Mismatch Repair at a Step Preceding DNA Resynthesis , 1996, Cell.

[21]  Benjamin Tycko,et al.  Creation of genomic methylation patterns , 1996, Nature Genetics.

[22]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[23]  J. Herman,et al.  Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. , 1996, Cancer research.

[24]  H. Ng,et al.  Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. , 1997, Science.

[25]  J. Herman,et al.  Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  F. Ledeist,et al.  An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. , 1993, Human molecular genetics.

[27]  A. Wolffe,et al.  DNA methylation in health and disease , 2000, Nature Reviews Genetics.

[28]  H. Leonhardt,et al.  A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei , 1992, Cell.

[29]  S. Timsit,et al.  Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein. , 1998, Human molecular genetics.

[30]  B. Maras,et al.  Nuclear matrix localization of annexin V in chicken liver. , 1996, Biochemical and biophysical research communications.

[31]  V. Ingram,et al.  Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J. Herman,et al.  CpG methylation is maintained in human cancer cells lacking DNMT1 , 2000, Nature.

[33]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[34]  C. Wijmenga,et al.  The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Herman,et al.  5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers , 1995, Nature Medicine.

[36]  T. Ono,et al.  Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. , 1994, Differentiation; research in biological diversity.

[37]  M. Lieber,et al.  CpG methylated minichromosomes become inaccessible for V(D)J recombination after undergoing replication. , 1992, The EMBO journal.

[38]  M. Ehrlich,et al.  DNA demethylation and pericentromeric rearrangements of chromosome 1. , 1997, Mutation research.

[39]  E. Li,et al.  Cloning, expression and chromosome locations of the human DNMT3 gene family. , 1999, Gene.

[40]  J. Rossignol,et al.  Suppression of crossing-over by DNA methylation in Ascobolus. , 1998, Genes & development.

[41]  Xiaodong Cheng,et al.  The DNA (cytosine-5) methyltransferases , 1994, Nucleic Acids Res..

[42]  R. Burdon,et al.  Nuclear matrix-associated DNA methylase. , 1985, Biochimica et biophysica acta.

[43]  C. Walsh,et al.  Transcription of IAP endogenous retroviruses is constrained by cytosine methylation , 1998, Nature Genetics.

[44]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[45]  V. Ingram,et al.  Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. , 1988, Journal of molecular biology.

[46]  J. Johnson,et al.  Characterization of a novel 23-kilodalton protein of unactive progesterone receptor complexes , 1994, Molecular and cellular biology.

[47]  Z. Kelman.  PCNA: structure, functions and interactions , 1997, Oncogene.

[48]  G. Verdine,et al.  Mammalian DNA cytosine‐5 methyltransferase interacts with p23 protein , 1996, FEBS letters.

[49]  A. Feinberg,et al.  Reduced genomic 5-methylcytosine content in human colonic neoplasia. , 1988, Cancer research.

[50]  S. Antonarakis,et al.  Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. , 2000, Genomics.

[51]  J. Herman,et al.  DNA hypermethylation in tumorigenesis: epigenetics joins genetics. , 2000, Trends in genetics : TIG.

[52]  John H. Walker,et al.  Subcellular localization of annexin V in human foreskin fibroblasts: nuclear localization depends on growth state , 1996, FEBS letters.

[53]  Nathan M. Springer,et al.  Conserved plant genes with similarity to mammalian de novo DNA methyltransferases. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Walsh,et al.  Cytosine methylation and the ecology of intragenomic parasites. , 1997, Trends in genetics : TIG.

[55]  J. Weissenbach,et al.  A sex chromosome rearrangement in a human XX male caused by Alu—Alu recombination , 1987, Cell.

[56]  J. Herman,et al.  In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[57]  B Johansson,et al.  Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. , 1997, Cancer research.

[58]  S. Baylin,et al.  Hypomethylation of pericentromeric DNA in breast adenocarcinomas , 1998, International journal of cancer.

[59]  F. Ishikawa,et al.  MBD2‐MBD3 complex binds to hemi‐methylated DNA and forms a complex containing DNMT1 at the replication foci in late S phase , 2000, Genes to cells : devoted to molecular & cellular mechanisms.

[60]  R. Roberts,et al.  Hhal methyltransferase flips its target base out of the DNA helix , 1994, Cell.

[61]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[62]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[63]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[64]  M. Caligiuri,et al.  Aberrant CpG-island methylation has non-random and tumour-type–specific patterns , 2000, Nature Genetics.

[65]  E. Li,et al.  Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. , 1998, Nucleic acids research.

[66]  M. Ehrlich,et al.  Satellite DNA hypomethylation vs. overall genomic hypomethylation in ovarian epithelial tumors of different malignant potential. , 1999, Mutation research.

[67]  R. Jaenisch,et al.  DNA Methyltransferase Contributes to Delayed Ischemic Brain Injury , 2000, The Journal of Neuroscience.

[68]  A. Bird,et al.  Effects of DNA methylation on DNA-binding proteins and gene expression. , 1993, Current opinion in genetics & development.

[69]  J. Herman,et al.  Hypermethylation of the DAP-kinase CpG island is a common alteration in B-cell malignancies. , 1999, Blood.

[70]  T. Kouzarides,et al.  Retinoblastoma protein meets chromatin. , 1999, Trends in biochemical sciences.

[71]  R J Roberts,et al.  Recombinant Human DNA (Cytosine-5) Methyltransferase , 1999, The Journal of Biological Chemistry.

[72]  P N Barlow,et al.  The solution structure of the domain from MeCP2 that binds to methylated DNA. , 1999, Journal of molecular biology.

[73]  T. Hashimshony,et al.  DNA methylation models histone acetylation , 1998, Nature.

[74]  T. Gibson,et al.  The PHD finger: implications for chromatin-mediated transcriptional regulation. , 1995, Trends in biochemical sciences.

[75]  M. Ehrlich,et al.  DNA hypomethylation and unusual chromosome instability in cell lines fromICF syndrome patients , 2000, Cytogenetic and Genome Research.

[76]  R. Jaenisch,et al.  Development: DNA methylation in Drosophila melanogaster , 2000, Nature.

[77]  F. Speleman,et al.  A human modifier of methylation for class I HLA genes (MEMO-1) maps to chromosomal bands 1p35-36.1. , 1996, Human molecular genetics.

[78]  R. Blaese,et al.  Variable immunodeficiency with abnormal condensation of the heterochromatin of chromosomes 1, 9, and 16. , 1988, The Journal of pediatrics.

[79]  A. Bird,et al.  Identification and Characterization of a Family of Mammalian Methyl-CpG Binding Proteins , 1998, Molecular and Cellular Biology.

[80]  K. Robertson,et al.  The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. , 1999, Nucleic acids research.

[81]  M. Kastan,et al.  Methylation of deoxycytidine incorporated by excision-repair synthesis of DNA , 1982, Cell.

[82]  J. Rice,et al.  Transcriptional repression of BRCA1 by aberrant cytosine methylation, histone hypoacetylation and chromatin condensation of the BRCA1 promoter. , 2000, Nucleic acids research.

[83]  S. Baylin,et al.  Increased cytosine DNA-methyltransferase activity during colon cancer progression. , 1993, Journal of the National Cancer Institute.

[84]  E. Li,et al.  Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases , 1998, Nature Genetics.

[85]  K. Muegge,et al.  Lsh, an SNF2/helicase family member, is required for proliferation of mature T lymphocytes. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[86]  A. Levine,et al.  Surfing the p53 network , 2000, Nature.

[87]  H. Pollard,et al.  A rise in nuclear calcium translocates annexins IV and V to the nuclear envelope , 1996, FEBS letters.

[88]  G. Lenoir,et al.  A 1-kb Alu-mediated germ-line deletion removing BRCA1 exon 17. , 1997, Cancer research.

[89]  E Gabrielson,et al.  Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[90]  R. Jaenisch,et al.  Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[91]  R. Jaenisch,et al.  Baculovirus-mediated expression and characterization of the full-length murine DNA methyltransferase. , 1997, Nucleic acids research.

[92]  S. Baylin,et al.  Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon , 1994, Nature Genetics.

[93]  E. Oakeley,et al.  Multiple domains are involved in the targeting of the mouse DNA methyltransferase to the DNA replication foci. , 1998, Nucleic acids research.

[94]  R. Jaenisch,et al.  Loss of methylation activates Xist in somatic but not in embryonic cells. , 1995, Genes & development.

[95]  A. Sancar,et al.  Purification of PCNA as a nucleotide excision repair protein. , 1992, Nucleic Acids Research.

[96]  T. Bestor,et al.  A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. , 1998, Human molecular genetics.

[97]  V. Kosma,et al.  Hypermethylation of the APC (adenomatous Polyposis Coli) gene promoter region in human colorectal carcinoma , 1997, International journal of cancer.

[98]  B. Stillman,et al.  Replication-Dependent Marking of DNA by PCNA Facilitates CAF-1-Coupled Inheritance of Chromatin , 1999, Cell.

[99]  A. Feinberg,et al.  Hypomethylation of DNA from benign and malignant human colon neoplasms. , 1985, Science.

[100]  C. Hsieh.  In Vivo Activity of Murine De Novo Methyltransferases, Dnmt3a and Dnmt3b , 1999, Molecular and Cellular Biology.

[101]  A. Niveleau,et al.  Abnormal methylation pattern in constitutive and facultative (X inactive chromosome) heterochromatin of ICF patients. , 1994, Human molecular genetics.

[102]  S. Baylin,et al.  De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase , 1996, Molecular and cellular biology.

[103]  J. Sawyer,et al.  Chromosome instability in ICF syndrome: formation of micronuclei from multibranched chromosomes 1 demonstrated by fluorescence in situ hybridization. , 1995, American journal of medical genetics.

[104]  Matthias Merkenschlager,et al.  Association of Transcriptionally Silent Genes with Ikaros Complexes at Centromeric Heterochromatin , 1997, Cell.

[105]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[106]  Stanley N Cohen,et al.  tsg101: A Novel Tumor Susceptibility Gene Isolated by Controlled Homozygous Functional Knockout of Allelic Loci in Mammalian Cells , 1996, Cell.

[107]  S. Hirohashi,et al.  Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[108]  A. Bird,et al.  Number of CpG islands and genes in human and mouse. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[109]  S. Warren,et al.  Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats , 1997, Nature Genetics.

[110]  Brian J. Reid,et al.  Progressive Region-Specific De Novo Methylation of the p16 CpG Island in Primary Human Mammary Epithelial Cell Strains during Escape from M0 Growth Arrest , 1999, Molecular and Cellular Biology.

[111]  J. Herman,et al.  Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Peter A. Jones,et al.  The Human ARF Cell Cycle Regulatory Gene Promoter Is a CpG Island Which Can Be Silenced by DNA Methylation and Down-Regulated by Wild-Type p53 , 1998, Molecular and Cellular Biology.

[113]  N. Dyson.  The regulation of E2F by pRB-family proteins. , 1998, Genes & development.

[114]  R. Beart,et al.  Methylation of the 5' CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. , 1995, Cancer research.

[115]  S. Baylin,et al.  DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci , 2000, Nature Genetics.

[116]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[117]  A. Bird,et al.  Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA , 1992, Cell.

[118]  D. Higgs,et al.  ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome. , 1996, Human molecular genetics.

[119]  Y. Imai,et al.  Molecular Cloning and Characterization of Annexin V‐Binding Proteins with Highly Hydrophilic Peptide Structure , 1996, Journal of neurochemistry.

[120]  Rudolf Jaenisch,et al.  Role for DNA methylation in genomic imprinting , 1993, Nature.

[121]  J. Brooks,et al.  Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[122]  J. Buchner,et al.  Hsp90 & Co. - a holding for folding. , 1999, Trends in biochemical sciences.

[123]  M. Ehrlich,et al.  Hypersensitivity to radiation-induced non-apoptotic and apoptotic death in cell lines from patients with the ICF chromosome instability syndrome. , 2000, Mutation research.

[124]  S. Kochanek,et al.  Transcriptional silencing of human Alu sequences and inhibition of protein binding in the box B regulatory elements by 5′‐CG‐3′ methylation , 1995, FEBS letters.

[125]  C. Wijmenga,et al.  Localization of the ICF syndrome to chromosome 20 by homozygosity mapping. , 1998, American journal of human genetics.

[126]  D. Higgs,et al.  Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation , 2000, Nature Genetics.

[127]  K. Robertson,et al.  Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. , 2000, Nucleic acids research.

[128]  N. Tommerup,et al.  Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene , 1999, Nature.

[129]  J. Jouanneau,et al.  Metastatic rat carcinoma cells express a new retrotransposon. , 1999, Gene.

[130]  J. Jeddeloh,et al.  Maintenance of genomic methylation requires a SWI2/SNF2-like protein , 1999, Nature Genetics.

[131]  S. Baylin,et al.  New 5′ Regions of the Murine and Human Genes for DNA (Cytosine-5)-methyltransferase* , 1996, The Journal of Biological Chemistry.

[132]  A. Feinberg,et al.  Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[133]  G. Hannon,et al.  The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA , 1994, Nature.

[134]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[135]  Luke Hughes-Davies,et al.  DNA methyltransferase Dnmt1 associates with histone deacetylase activity , 2000, Nature Genetics.

[136]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.