Methylation and Cancer

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Methylation and Cancer
Andrew J. Pierce
Microbiology, Immunology and Molecular
Genetics Graduate Center for Toxicology Markey
Cancer Center University of Kentucky
MI616 Spring 2007
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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
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Single Carbon Transfers
DNMT
cytosine
5-methylcytosine
http//www.hscbklyn.edu/SUNY/Biochem/ALCOHOL/alcoh
ol_folate_bkgd.html
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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 1221(35)5380-7.
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Geometry of 5-methycytosine
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Model for methyl-directed gene deactivation
Robertson KD. DNA methylation and chromatin -
unraveling the tangled web. Oncogene. 2002 Aug
1221(35)5361-79.
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Genes altered by cytosine methylation in cancer
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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 1221(35)5427-40.
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11 different tumor-supressor genes
Esteller M. CpG island hypermethylation and tumor
suppressor genes a booming present, a brighter
future. Oncogene. 2002 Aug 1221(35)5427-40.
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Chemotherapy and reactivation of methylated genes
cytidine analogs irreversibly bind DNMTs 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 1221(35)5483-95.
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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 1221(35)5483-95.
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Methylation based cancer screening
Das PM, Singal R. DNA methylation and cancer. J
Clin Oncol. 2004 Nov 1522(22)4632-42.
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Histone methylation
Rice JC, Allis CD. Histone methylation versus
histone acetylation new insights into epigenetic
regulation. Curr Opin Cell Biol. 2001
Jun13(3)263-73.\
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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
29119(7)941-53.
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Methotrexate mediated inactivation of RAS?