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|Title:||Selective depletion of human DNA-methyltransferase DNMT1 proteins by sulfonate-derived methylating agents||Authors:||Chuang, L.S.-H.
|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||URI:||http://scholarbank.nus.edu.sg/handle/10635/112064||ISSN:||00085472|
|Appears in Collections:||Staff Publications|
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