期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 16, 页码 12622-12633出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.313429
关键词
-
资金
- National Natural Science Foundation of China [30770831, 81000893, 30800413, 30873094, 81090421]
- Ministry of Education of China [J20100041]
- Zhejiang Provincial Science Foundation [R207153, 2008C23070, J20110353]
DNA polymerase eta (Pol eta) implements translesion DNA synthesis but has low fidelity in replication. We have previously shown that Pol eta plays an important role in the genesis of non-targeted mutations at undamaged DNA sites in cells exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Here, we report that MNNG-induced Pol eta expression in an interferon regulatory factor 1 (IRF1)-dependent manner in human cells. Mutagenesis analysis showed that four critical residues (Arg-82, Cys-83, Asn-86, and Ser-87) located in the IRF family conserved DNA binding domain-helix alpha 3 were involved in DNA binding and POLH transactivation by IRF1. Furthermore, Pol eta up-regulation induced by IRF1 was responsible for the increase of mutation frequency in a SupF shuttle plasmid replicated in the MNNG-exposed cells. Interestingly, IRF1 was acetylated by the histone acetyltransferase CBP in these cells. Lys -> Arg substitution revealed that Lys-78 of helix alpha 3 was the major acetylation site, and the IRF1-K78R mutation partially inhibited DNA binding and its transcriptional activity. Thus, we propose that IRF1 activation is responsible for MNNG-induced Pol eta up-regulation, which contributes to mutagenesis and ultimately carcinogenesis in cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据