In vivo evidence that DNA polymerase kappa is responsible for error-free bypass across DNA cross-links induced by mitomycin C

作者：Takeiri Akira^*; Wada Naoko A; Motoyama Shigeki; Matsuzaki Kaori; Tateishi Hiromi; Matsumoto Kaoru; Niimi Naoko; Sassa Akira; Gruz Petr; Masumura Kenichi; Yamada Masami; Mishima Masayuki; Jishage Kou ichi; Nohmi Takehiko

来源：DNA Repair, 2014, 24: 113-121.

DOI：10.1016/j.dnarep.2014.09.002

• DNA polymerase kappa
• Knock-in mice
• Gpt delta mice
• Cross-links
• Mitomycin C

Translesion DNA synthesis (TLS) is an important pathway that avoids genotoxicity induced by endogenous and exogenous agents. DNA polymerase kappa (Polk) is a specialized DNA polymerase involved in TLS but its protective roles against DNA damage in vivo are still unclear. To better understand these roles, we have established knock-in mice that express catalytically-inactive Polk and crossbred them with gpt delta mice, which possess reporter genes for mutations. The resulting mice (inactivated Polk KI mice) were exposed to mitomycin C (MMC), and the frequency of point mutations, micronucleus formation in peripheral erythrocytes, and gamma H2AX induction in the bone marrow was determined. The inactivated Polk KI mice exhibited significantly higher frequency of mutations at CpG and GpG sites, micronucleated cells, and gamma H2AX foci-positive cells than did the Polk wild-type (Polk(+)) mice. Recovery from MMC-induced DNA damage, which was evaluated by gamma H2AX induction, was retarded in embryonic fibroblasts from the knock-in mice when compared to those from the Polk(+) mice. These results suggest that Polk mediates TLS, which suppresses point mutations and DNA double-strand breaks caused by intra- and interstrand cross-links induced by MMC treatment. The established knock-in mice are extremely useful to elucidate the in vivo roles of the catalytic activity of Polk in suppressing DNA damage that was induced by a variety of genotoxic stresses.

• 出版日期2014-12
• 单位河北医科大学