Download Methylation

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
• cytosine demethylation activating genes
• histone methylation in chromatin (eg. H3 lys4)
• response to methylating chemotherapy drugs
temozolomide
O6-methyl guanine
Single Carbon Transfers
cytosine
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http://www.hscbklyn.edu/SUNY/Biochem/ALCOHOL/alcohol_folate_bkgd.html
DNMT
5-methylcytosine
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
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Clark SJ, Melki J.
DNA methylation and gene silencing in cancer: which is the guilty party?
Oncogene. 2002 Aug 12;21(35):5380-7.
Geometry of 5-methycytosine
G : 5-MeC
G:C
A:T
Model for methyl-directed gene deactivation
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Robertson KD.
DNA methylation and chromatin - unraveling the tangled web.
Oncogene. 2002 Aug 12;21(35):5361-79.
Genes altered by cytosine methylation in cancer
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 deactivated by methylation in human cancers
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Esteller M.
CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.
Oncogene. 2002 Aug 12;21(35):5427-40.
11 different tumor-supressor genes
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Esteller M.
CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future.
Oncogene. 2002 Aug 12;21(35):5427-40.
Chemotherapy and reactivation of methylated genes
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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.
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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 12;21(35):5483-95.
Methylation based cancer screening
Das PM, Singal R.
DNA methylation and cancer.
J Clin Oncol. 2004 Nov 15;22(22):4632-42.
Histone methylation
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Rice JC, Allis CD.
Histone methylation versus histone acetylation: new insights into epigenetic regulation.
Curr Opin Cell Biol. 2001 Jun;13(3):263-73.\
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.
Methotrexate mediated inactivation of RAS?