Variable effects of DNA-synthesis inhibitors upon DNA methylation in mammalian cells.

AUTOR(ES)

Nyce, J

RESUMO

Post-synthetic enzymatic hypermethylation of DNA was induced in hamster fibrosarcoma cells by the DNA synthesis inhibitors cytosine arabinoside, hydroxyurea and aphidicolin. This effect required direct inhibition of DNA polymerase alpha or reduction in deoxynucleotide pools and was not specific to a single cell type. At equivalently reduced levels of DNA synthesis, neither cycloheximide, actinomycin D nor serum deprivation affected DNA methylation in this way. The topoisomerase inhibitors nalidixic acid and novobiocin caused significant hypomethylation indicating that increased 5-mCyt content was not a necessary consequence of DNA synthesis inhibition. The induced hypermethylation occurred predominantly in that fraction of the DNA synthesized in the presence of inhibitor; was stable in the absence of drug; was most prominent in low molecular weight DNA representing sites of initiated but incomplete DNA synthesis; and occurred primarily within CpG dinucleotides, although other dinucleotides were overmethylated as well. Drug-induced CpG hypermethylation may be capable of silencing genes, an effect which may be relevant to the aberrantly expressed genes characteristic of neoplastic cells.

Documentos Relacionados

• A kinetic study of lung DNA-synthesis during simulated chronic high altitude hypoxia.
• DNA-synthesis with methylated poly(dA-dT) templates: possible role of O4-methylthymine as a pro-mutagenic base.
• DNA methylation and transcriptional controls of proviral DNA in avian sarcoma virus-transformed mammalian cells.
• Effects of methotrexate on transfected DNA stability in mammalian cells.
• Spreading of DNA methylation across integrated foreign (adenovirus type 12) genomes in mammalian cells.