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Title: Selective depletion of human DNA-methyltransferase DNMT1 proteins by sulfonate-derived methylating agents
Authors: Chuang, L.S.-H. 
Tan, E.H.-H. 
Oh, H.-K.
Li, B.F.-L. 
Issue Date: 15-Mar-2002
Citation: Chuang, L.S.-H.,Tan, E.H.-H.,Oh, H.-K.,Li, B.F.-L. (2002-03-15). Selective depletion of human DNA-methyltransferase DNMT1 proteins by sulfonate-derived methylating agents. Cancer Research 62 (6) : 1592-1597. ScholarBank@NUS Repository.
Abstract: 5-Methylcytosine residues in the DNA (DNA methylation) are formed from the transfer of the methyl group from S-adenosylmethionine to the C-5 position of cytosine by the DNA-(cytosine-5) methyltransferases (DNMTs). Although regional hypermethylation and global hypomethylation of the genome are commonly observed in neoplastic cells, how these aberrant methylation patterns occur remains unestablished. We report here that sulfonate-derived methylating agents, unlike N-methylnitrosourea or iodomethane, are potent in depleting DNMT1 proteins in human cells, in addition to their DNA-damaging properties. Their effects on cellular DNMT1 are time and dosage dependent but independent of cell type. Unlike γ-irradiation, these agents apparently do not activate the p53/p21WAF1 DNA damage response pathway to deplete the DNMT1 proteins because cells with wild-type, mutated, or inactivated p53 behave similarly. However, cell cycle analysis and protease assay studies strongly suggest that methylmethanesulfonate may activate a cellular protease to degrade DNMT1. These results explain why reported observations on the effect of alkylating agents on DNMT1 activities in human cells vary significantly and provide a crucial link to understand the mechanism behind genomic hypomethylation.
Source Title: Cancer Research
ISSN: 00085472
Appears in Collections:Staff Publications

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