Wu Xiaohua, Takenaka Katsuya, Sonoda Eiichiro, Hochegger Helfrid, Kawanishi Shosuke, Kawamoto Takuo, Takeda Shunichi, Yamazoe Mitsuyoshi
Department of Radiation Genetics, Graduate School of Medicine, Kyoto University, Yoshida Konoe, Sakyo-ku, Kyoto 606-8501, Japan.
Cancer Res. 2006 Jan 15;66(2):748-54. doi: 10.1158/0008-5472.CAN-05-2884.
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.
一氧化氮（NO）是一种参与炎症以及平滑肌和神经元调节的信号传递分子，似乎会导致诱变，但其机制仍不清楚。为深入了解NO诱导的基因毒性，我们分析了NO对一组缺乏DNA修复途径（包括碱基和核苷酸切除修复、双链断裂修复以及跨损伤DNA合成（TLS））的鸡DT40克隆的影响。我们的结果表明，缺乏Rev1和Rev3（DNA聚合酶ζ（Polζ）必需的一个亚基）的细胞对两种化学NO供体（精胺亚硝基铁氰化钠和S-亚硝基-N-乙酰青霉胺）的杀伤作用高度敏感。有丝分裂染色体分析表明，这种高度敏感性是由诱导染色体断裂水平的显著增加引起的。数据揭示了TLS聚合酶在细胞对NO诱导的DNA损伤耐受性中的关键作用，并表明这些易出错的聚合酶对单碱基替换积累的作用。
