Nitric oxide inhibits DNA-adduct excision in nucleotide excision repair.
Sustained induction of nitric oxide (NO) in chronic inflammation may be mutagenic, through DNA damage induction and/or DNA repair inhibition. Although there is good evidence that NO can cause DNA damage, how NO is involved in DNA repair remains elusive. By using DNA synthesis inhibitors to accumulate DNA strand breaks in comet assay, we show that NO and peroxynitrite inhibit DNA-adduct excision in human fibroblasts damaged by UVC, 4-nitroquinoline 1-oxide, benzo[a]pyrene dihydrodiol epoxide, cisplatin, or mitomycin C, but not with methyl methane sulfonate. Treating cells with arsenite increased NO production and also inhibited the DNA-adduct excision induced by UVC, 4-nitroquinoline 1-oxide, benzo[a]pyrene dihydrodiol epoxide, cisplatin, and mitomycin C, but not by methyl methane sulfonate, H(2)O(2), sodium nitrosoprusside, or 3-morpholinosydnonimine. Arsenite inhibition of DNA-adduct excision was decreased by NO synthase inhibitors and NO scavengers. The nuclear extract prepared from fibroblasts pretreated with sodium nitrosoprusside, dipropylenetriamine NONOate, 3-morpholinosydnonimine, or arsenite also showed decreased activity in excising the DNA adducts induced by UVC and cisplatin but not by methyl methane sulfonate or H(2)O(2) plus Fe. These results are consistent with the notion that NO, peroxynitrite, and arsenite inhibit the DNA-adduct excision in nucleotide excision repair but not that in base excision repair.
Chien
Yuan-Hung
YH
Institute of Zoology, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
Bau
Da-Tian
DT
Jan
Kun-Yan
KY
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D020552:Comet Assay; D004247:DNA; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays
D000477:Alkylating Agents; D018053:Arsenites; D018736:DNA Adducts; D020030:Nitric Oxide Donors; C043931:benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide-DNA; D009599:Nitroprusside; D009569:Nitric Oxide; D016685:Mitomycin; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D015112:4-Nitroquinoline-1-oxide; C002385:linsidomine; D004247:DNA; D008981:Molsidomine; D002945:Cisplatin