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

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 temozolomideO 6 -methyl guanine

cytosine5-methylcytosine DNMT Single Carbon Transfers

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 Aug 12;21(35):

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

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

Genes altered by cytosine methylation in cancer Rb (tumor supressor) Mlh1 (mismatch repair) VHL (oxidative stress response) p16 INK4A (CDK inhibitor) CpG island hypermethylation Inactivation Activation parasitic sequences eg: retrotransposons activate homologous recombination?

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

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

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 Aug 12;21(35):

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

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

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

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 Dec 29;119(7): A “real” histone demethylase

Methotrexate mediated inactivation of RAS?