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Methylation and Cancer

Methylation and Cancer. Andrew J. Pierce. Microbiology, Immunology and Molecular Genetics Graduate Center for Toxicology Markey Cancer Center University of Kentucky. MI616 Spring 2007. Some considerations of methylation in cancer:. cytosine methylation inactivating genes

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Methylation and Cancer

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  1. Methylation and Cancer Andrew J. Pierce Microbiology, Immunology and Molecular Genetics Graduate Center for Toxicology Markey Cancer Center University of Kentucky MI616 Spring 2007

  2. Some considerations of methylation in cancer: • cytosine methylation inactivating genes • cytosine demethylation activating genes • histone methylation in chromatin (eg. H3 lys4) • response to methylating chemotherapy drugs temozolomide O6-methyl guanine

  3. Single Carbon Transfers DNMT cytosine 5-methylcytosine http://www.hscbklyn.edu/SUNY/Biochem/ALCOHOL/alcohol_folate_bkgd.html

  4. 5-methylcytosine • Occurs on CpG sequences • CpG is under-represented in the genome • CpG is over-represented near promoter sequences • reset at fertilization and established early in embryogenesis Clark SJ, Melki J. DNA methylation and gene silencing in cancer: which is the guilty party? Oncogene. 2002 Aug 12;21(35):5380-7.

  5. G : 5-MeC G : C A : T Geometry of 5-methycytosine

  6. Model for methyl-directed gene deactivation Robertson KD. DNA methylation and chromatin - unraveling the tangled web. Oncogene. 2002 Aug 12;21(35):5361-79.

  7. Inactivation • Rb (tumor supressor) • Mlh1 (mismatch repair) • VHL (oxidative stress response) • p16INK4A (CDK inhibitor) • CpG island hypermethylation Activation • parasitic sequences eg: retrotransposons • activate homologous recombination? Genes altered by cytosine methylation in cancer

  8. Genes deactivated by methylation in human cancers Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002 Aug 12;21(35):5427-40.

  9. 11 different tumor-supressor genes Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002 Aug 12;21(35):5427-40.

  10. Chemotherapy and reactivation of methylated genes cytidine analogs irreversibly bind DNMT’s leading to genome-wide demethylation Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002 Aug 12;21(35):5483-95.

  11. Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002 Aug 12;21(35):5483-95.

  12. Methylation based cancer screening Das PM, Singal R. DNA methylation and cancer. J Clin Oncol. 2004 Nov 15;22(22):4632-42.

  13. Histone methylation Rice JC, Allis CD. Histone methylation versus histone acetylation: new insights into epigenetic regulation. Curr Opin Cell Biol. 2001 Jun;13(3):263-73.\

  14. A “real” histone demethylase Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004 Dec 29;119(7):941-53.

  15. Methotrexate mediated inactivation of RAS?

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