Damage proneness induced by genomic DNA demethylation in mammalian cells cultivated in vitro.
Variations in the genomic DNA methylation level have been shown to be an epigenetic inheritable modification affecting, among other targets, the sister chromatid exchange (SCE) rate in mammalian cells in vitro. The inheritable increase in SCE rate in affected cell populations appears as a puzzling phenomenon in view of the well established relation between SCE and both mutagenesis and carcinogenesis. In the present work we demonstrate that, in a treated cell population, demethylation could be responsible for the inheritable induction of damage proneness affecting both damage induction and repair. Normal and ethionine or azacytidine treated Chinese hamster ovary cells, subclone K1 (CHO-K1), were challenged with UV light (UV) or mitomycin-C (MMC) at different times from the demethylating treatment. The SCE rate was measured with two main objects in view: (i) the induction of synergism or additivity in combined treatments, where mutagen (UV or MMC) pulse is supplied from 0 to 48 h after the end of the demethylating treatment; and (ii) the pattern of damage extinction, for the duration of up to six cell cycles after the end of the combined (demethylating agent + mutagen) treatment. Results indicate both a synergism in SCE induction by mutagens in demethylated cells even if supplied up to four cell cycles after the end of the demethylation treatment and a delay in recovery of induced damage, compared with normally methylated cells. These data are discussed in the light of the supposed mechanism of SCE increase and of the possible biological significance in terms of mutagenesis and carcinogenesis.
Perticone
P
P
Centro di Genetica Evoluzionistica del CNR, Dipartimento di Genetica e Biologia Molecolare, Università La Sapienza, Roma, Italy.
Gensabella
G
G
Cozzi
R
R
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics* / Q000528:radiation effects; D019175:DNA Methylation / Q000187:drug effects* / Q000528:radiation effects; D004357:Drug Synergism; D005001:Ethionine / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D012854:Sister Chromatid Exchange; D014466:Ultraviolet Rays
D000963:Antimetabolites; D002273:Carcinogens; D009153:Mutagens; D019384:Nucleic Acid Synthesis Inhibitors; D016685:Mitomycin; D001374:Azacitidine; D005001:Ethionine