Human Molecular Genetics, Vol 3, 1487-1495, Copyright © 1994 by Oxford University Press
PW Laird and R Jaenisch
Changes in the pattern of DNA methylation have been a consistent finding in
cancer cells. The mostly descriptive nature of these studies and the fact
that both hypo- and hypermethylation have been observed at various loci
have made it difficult to assess whether these changes are causally
involved in the transformation process or whether they reflect the altered
physiology of rapidly dividing cancer cells. It is clear, however, that DNA
methylation plays an important role in the generation of mutations in human
tumors. The high incidence of C-to-T transitions found in the p53
tumor-suppressor gene is attributed to the spontaneous deamination of
5-methylcytosine residues. The multiple observations linking DNA
methylation to cancer can be resolved in a model proposing that the high
rate of mutation at CpG dinucleotides is due in part to
methyltransferase-facilitated deamination. Support for a role of DNA
methyltransferase as a mutator enzyme is provided by work with a
prokaryotic DNA methyltransferase under S-adenosyl-methionine methyl- donor
limiting conditions. Methyl-donor limiting conditions might arise in early
stages of tumor development, leading to high rates of
methyltransferase-mediated CpG mutagenesis, as seen in human tumors. Such a
mechanism is consistent with the frequently reported methionine auxotrophy
of cancer cells and with the tumorigenic effects of methyl- deficient
diets. Methyl deficiency in tumor cells is also consistent with the
commonly observed global hypomethylation of tumor cell DNA, despite normal
or even high levels of DNA methyltransferase expression.
REVIEWS
DNA methylation and cancer
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Rival, E. Jaligot, T. Beule, and E. J. Finnegan Isolation and expression analysis of genes encoding MET, CMT, and DRM methyltransferases in oil palm (Elaeis guineensis Jacq.) in relation to the 'mantled' somaclonal variation J. Exp. Bot., September 1, 2008; 59(12): 3271 - 3281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Clark Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis Hum. Mol. Genet., April 15, 2007; 16(R1): R88 - R95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Widodo, C. C. Deocaris, K. Kaur, K. Hasan, T. Yaguchi, K. Yamasaki, T. Sugihara, T. Ishii, R. Wadhwa, and S. C. Kaul Stress Chaperones, Mortalin, and Pex19p Mediate 5-Aza-2' Deoxycytidine-Induced Senescence of Cancer Cells by DNA Methylation-Independent Pathway J. Gerontol. A Biol. Sci. Med. Sci., March 1, 2007; 62(3): 246 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Khalkhali-Ellis Maspin: The New Frontier Clin. Cancer Res., December 15, 2006; 12(24): 7279 - 7283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mizuno, S. Tokuoka, M. Kishikawa, E. Nakashima, K. Mabuchi, and K. S. Iwamoto Molecular basis of basal cell carcinogenesis in the atomic-bomb survivor population: p53 and PTCH gene alterations Carcinogenesis, November 1, 2006; 27(11): 2286 - 2294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-C. Chou, M.-H. Wu, J.-C. Yu, M.-S. Lee, T. Yang, H.-L. Shih, T.-Y. Wu, and C.-A. Sun Genetic polymorphisms of the methylenetetrahydrofolate reductase gene, plasma folate levels and breast cancer susceptibility: a case-control study in Taiwan Carcinogenesis, November 1, 2006; 27(11): 2295 - 2300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Rodenhiser and M. Mann Epigenetics and human disease: translating basic biology into clinical applications Can. Med. Assoc. J., January 31, 2006; 174(3): 341 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Melnikov, R. B. Gartenhaus, A. S. Levenson, N. A. Motchoulskaia, and V. V. Levenson (Chernokhvostov) MSRE-PCR for analysis of gene-specific DNA methylation Nucleic Acids Res., June 8, 2005; 33(10): e93 - e93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Frigola, X. Sole, M. F. Paz, V. Moreno, M. Esteller, G. Capella, and M. A. Peinado Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer Hum. Mol. Genet., January 15, 2005; 14(2): 319 - 326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Mo and C. E. Elson Studies of the Isoprenoid-Mediated Inhibition of Mevalonate Synthesis Applied to Cancer Chemotherapy and Chemoprevention Experimental Biology and Medicine, July 1, 2004; 229(7): 567 - 585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. D. Allen and D. L. Nuss Specific and Common Alterations in Host Gene Transcript Accumulation following Infection of the Chestnut Blight Fungus by Mild and Severe Hypoviruses J. Virol., April 15, 2004; 78(8): 4145 - 4155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Crott, S.-W. Choi, J. M. Ordovas, J. S. Ditelberg, and J. B. Mason Effects of dietary folate and aging on gene expression in the colonic mucosa of rats: implications for carcinogenesis Carcinogenesis, January 1, 2004; 25(1): 69 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. James, I. P. Pogribny, M. Pogribna, B. J. Miller, S. Jernigan, and S. Melnyk Mechanisms of DNA Damage, DNA Hypomethylation, and Tumor Progression in the Folate/Methyl-Deficient Rat Model of Hepatocarcinogenesis J. Nutr., November 1, 2003; 133(11): 3740S - 3747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-W. Yang, S. Liu, Y. Tian, H. R. Salwen, A. Chlenski, J. Weinstein, and S. L. Cohn Methylation-associated Silencing of the Thrombospondin-1 Gene in Human Neuroblastoma Cancer Res., October 1, 2003; 63(19): 6299 - 6310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Hiltunen and S. Yla-Herttuala DNA Methylation, Smooth Muscle Cells, and Atherogenesis Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1750 - 1753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hori, S. Yonei, H. Sugiyama, K. Kino, K. Yamamoto, and Q.-M. Zhang Identification of high excision capacity for 5-hydroxymethyluracil mispaired with guanine in DNA of Escherichia coli MutM, Nei and Nth DNA glycosylases Nucleic Acids Res., February 15, 2003; 31(4): 1191 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Sekigawa, M Okada, H Ogasawara, H Kaneko, T Hishikawa, and H Hashimoto DNA methylation in systemic lupus erythematosus Lupus, February 1, 2003; 12(2): 79 - 85. [Abstract] [PDF]
|
|
|
|
 |
|
 M. M. de Jong, I. M. Nolte, G. J. te Meerman, W. T. A. van der Graaf, E. G. E. de Vries, R. H. Sijmons, R. M. W. Hofstra, and J. H. Kleibeuker Low-penetrance Genes and Their Involvement in Colorectal Cancer Susceptibility Cancer Epidemiol. Biomarkers Prev., November 1, 2002; 11(11): 1332 - 1352. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-S. Cong, W. E. Wright, and J. W. Shay Human Telomerase and Its Regulation Microbiol. Mol. Biol. Rev., September 1, 2002; 66(3): 407 - 425. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Watson and J. I. Goodman Effects of Phenobarbital on DNA Methylation in GC-Rich Regions of Hepatic DNA from Mice That Exhibit Different Levels of Susceptibility to Liver Tumorigenesis Toxicol. Sci., July 1, 2002; 68(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Chan, R. van Amerongen, T. Nijjar, E. Cuppen, P. A. Jones, and P. W. Laird Reduced Rates of Gene Loss, Gene Silencing, and Gene Mutation in Dnmt1-Deficient Embryonic Stem Cells Mol. Cell. Biol., November 15, 2001; 21(22): 7587 - 7600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Diaz-Cano, M. de Miguel, A. Blanes, R. Tashjian, and H. J. Wolfe Germline RET 634 Mutation Positive MEN 2A-related C-Cell Hyperplasias Have Genetic Features Consistent with Intraepithelial Neoplasia J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3948 - 3957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Crott, S. T. Mashiyama, B. N. Ames, and M. F. Fenech Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro Carcinogenesis, July 1, 2001; 22(7): 1019 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-i. Mizuno, T. Chijiwa, T. Okamura, K. Akashi, Y. Fukumaki, Y. Niho, and H. Sasaki Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia Blood, March 1, 2001; 97(5): 1172 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Macintyre, C. V. Atwood, and C. G. Cupples Lowering S-Adenosylmethionine Levels in Escherichia coli Modulates C-to-T Transition Mutations J. Bacteriol., February 1, 2001; 183(3): 921 - 927. [Abstract] [Full Text]
|
|
|
|
 |
|
 V. Rusmintratip and L. C. Sowers An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts PNAS, December 19, 2000; 97(26): 14183 - 14187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Rusmintratip, A. D. Riggs, and L. C. Sowers Examination of the DNA substrate selectivity of DNA cytosine methyltransferases using mass tagging Nucleic Acids Res., September 15, 2000; 28(18): 3594 - 3599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Liang, K. D. Robertson, C. Talmadge, J. Sumegi, and P. A. Jones The Gene for a Novel Transmembrane Protein Containing Epidermal Growth Factor and Follistatin Domains Is Frequently Hypermethylated in Human Tumor Cells Cancer Res., September 1, 2000; 60(17): 4907 - 4912. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. K. Ying, H. H. Hassanain, C. M. Roos, D. J. Smiraglia, J.-P. J. Issa, R. E. Michler, M. Caligiuri, C. Plass, and P. J. Goldschmidt-Clermont Methylation of the estrogen receptor-{alpha} gene promoter is selectively increased in proliferating human aortic smooth muscle cells Cardiovasc Res, April 1, 2000; 46(1): 172 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Shin, H.-S. Kim, J. Park, J.-B. Park, and J.-Y. Lee Mechanism for Inactivation of the KIP Family Cyclin-dependent Kinase Inhibitor Genes in Gastric Cancer Cells Cancer Res., January 1, 2000; 60(2): 262 - 265. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. J. Diaz-Cano, M. de Miguel, A. Blanes, R. Tashjian, H. Galera, and H. J. Wolfe Clonality as Expression of Distinctive Cell Kinetics Patterns in Nodular Hyperplasias and Adenomas of the Adrenal Cortex Am. J. Pathol., January 1, 2000; 156(1): 311 - 319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-W. Hsu, M.-J. Lin, T.-L. Lee, S.-C. Wen, X. Chen, and C.-K. J. Shen Two major forms of DNA (cytosine-5) methyltransferase in human somatic tissues PNAS, August 17, 1999; 96(17): 9751 - 9756. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Slattery, J. D. Potter, W. Samowitz, D. Schaffer, and M. Leppert Methylenetetrahydrofolate Reductase, Diet, and Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., June 1, 1999; 8(6): 513 - 518. [Abstract] [Full Text]
|
|
|
|
|
|
M. Nakayama, M. Wada, T. Harada, J. Nagayama, H. Kusaba, K. Ohshima, M. Kozuru, H. Komatsu, R. Ueda, and M. Kuwano Hypomethylation Status of CpG Sites at the Promoter Region and Overexpression of the Human MDR1 Gene in Acute Myeloid Leukemias Blood, December 1, 1998; 92(11): 4296 - 4307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Mikovits, H. A. Young, P. Vertino, J.-P. J. Issa, P. M. Pitha, S. Turcoski-Corrales, D. D. Taub, C. L. Petrow, S. B. Baylin, and F. W. Ruscetti Infection with Human Immunodeficiency Virus Type 1 Upregulates DNA Methyltransferase, Resulting in De Novo Methylation of the Gamma Interferon (IFN-gamma ) Promoter and Subsequent Downregulation of IFN-gamma Production Mol. Cell. Biol., September 1, 1998; 18(9): 5166 - 5177. [Abstract] [Full Text]
|
|
|
|
|
|
D. Macleod, R. R. Ali, and A. Bird An Alternative Promoter in the Mouse Major Histocompatibility Complex Class II I-Abeta Gene: Implications for the Origin of CpG Islands Mol. Cell. Biol., August 1, 1998; 18(8): 4433 - 4443. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. M. Swisher, D. G. Mutch, T. J. Herzog, J. S. Rader, L. D. Kowalski, A. Elbendary, and P. J. Goodfellow Analysis of MSH3 in Endometrial Cancers With Defective DNA Mismatch Repair Reproductive Sciences, July 1, 1998; 5(4): 210 - 216. [Abstract] [PDF]
|
|
|
|
|
|
T. Goto and M. Monk Regulation of X-Chromosome Inactivation in Development in Mice and Humans Microbiol. Mol. Biol. Rev., June 1, 1998; 62(2): 362 - 378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Ferguson, P. M. Vertino, J. R. Spitzner, S. B. Baylin, M. T. Muller, and N. E. Davidson Role of Estrogen Receptor Gene Demethylation and DNA Methyltransferase·DNA Adduct Formation in 5-Aza-2'deoxycytidine-induced Cytotoxicity In Human Breast Cancer Cells J. Biol. Chem., December 19, 1997; 272(51): 32260 - 32266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Gill, Y. Tsai, A. P. Rao, P. Jones, S. J. Diaz-Cano, H. J. Wolfe, C. S. Rabkin, S. Janz, and Z. Zhuang Clonality in Kaposi's Sarcoma N. Engl. J. Med., August 21, 1997; 337(8): 570 - 572. [Full Text]
|
|
|
|
|
|
L. He, H. Mo, S. Hadisusilo, A. A. Qureshi, and C. E. Elson Isoprenoids Suppress the Growth of Murine B16 Melanomas In Vitro and In Vivo J. Nutr., May 1, 1997; 127(5): 668 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Denissenko, J. X. Chen, M.-s. Tang, and G. P. Pfeifer Cytosine methylation determines hot spots of DNA damage in the human P53 gene PNAS, April 15, 1997; 94(8): 3893 - 3898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Peyruchaud, F. Bourre, M.-C. Morel-Kopp, D. Reviron, P. Mercier, A. Nurden, and C. Kaplan HPA-10wb (Laa): Genetic Determination of a New Platelet-Specific Alloantigen on Glycoprotein IIIa and Its Expression in COS-7 Cells Blood, April 1, 1997; 89(7): 2422 - 2428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Yoder, R.-W. C. Yen, P. M. Vertino, T. H. Bestor, and S. B. Baylin New 5' Regions of the Murine and Human Genes for DNA (Cytosine-5)-methyltransferase J. Biol. Chem., December 6, 1996; 271(49): 31092 - 31097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Tucker, D. Talbot, M. A. Lee, H. Leonhardt, and R. Jaenisch Complementation of methylation deficiency in embryonic stem cells by a DNA methyltransferase minigene PNAS, November 12, 1996; 93(23): 12920 - 12925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bandaru, J. Gopal, and A. S. Bhagwat Overproduction of DNA Cytosine Methyltransferases Causes Methylation and C [IMAGE] T Mutations at Non-canonical Sites J. Biol. Chem., March 29, 1996; 271(13): 7851 - 7859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Sun, G. Hegamyer, H. Kim, K. Sithanandam, H. Li, R. Watts, and N. H. Colburn Molecular Cloning of Mouse Tissue Inhibitor of Metalloproteinases-3 and Its Promoter J. Biol. Chem., August 18, 1995; 270(33): 19312 - 19319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Campanero, M. I. Armstrong, and E. K. Flemington CpG methylation as a mechanism for the regulation of E2F activity PNAS, June 6, 2000; 97(12): 6481 - 6486. [Abstract] [Full Text] [PDF]
|
|