Critical roles for polymerase zeta in cellular tolerance to nitric oxide-induced DNA damage.
Nitric oxide (NO), a signal transmitter involved in inflammation and regulation of smooth muscle and neurons, seems to cause mutagenesis, but its mechanisms have remained elusive. To gain an insight into NO-induced genotoxicity, we analyzed the effect of NO on a panel of chicken DT40 clones deficient in DNA repair pathways, including base and nucleotide excision repair, double-strand break repair, and translesion DNA synthesis (TLS). Our results show that cells deficient in Rev1 and Rev3, a subunit essential for DNA polymerase zeta (Polzeta), are hypersensitive to killing by two chemical NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine. Mitotic chromosomal analysis indicates that the hypersensitivity is caused by a significant increase in the level of induced chromosomal breaks. The data reveal the critical role of TLS polymerases in cellular tolerance to NO-induced DNA damage and suggest the contribution of these error-prone polymerases to accumulation of single base substitutions.
Wu
Xiaohua
X
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Takenaka
Katsuya
K
Sonoda
Eiichiro
E
Hochegger
Helfrid
H
Kawanishi
Shosuke
S
Kawamoto
Takuo
T
Takeda
Shunichi
S
Yamazoe
Mitsuyoshi
M
D000818:Animals; D018929:Cell Culture Techniques; D002645:Chickens; D002869:Chromosome Aberrations; D004249:DNA Damage; D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D009569:Nitric Oxide / Q000633:toxicity*; D009713:Nucleotidyltransferases / Q000502:physiology*; D017354:Point Mutation
D009569:Nitric Oxide; C425929:DNA polymerase zeta; D009713:Nucleotidyltransferases; D004259:DNA-Directed DNA Polymerase