title: Interferon regulatory factor 1 transactivates expression of human DNA polymerase η in response to carcinogen N-methyl-N'-nitro-N-nitrosoguanidine.
abstract: DNA polymerase η (Polη) implements translesion DNA synthesis but has low fidelity in replication. We have previously shown that Polη plays an important role in the genesis of nontargeted mutations at undamaged DNA sites in cells exposed to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Here, we report that MNNG-induced Polη 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 α3 were involved in DNA binding and POLH transactivation by IRF1. Furthermore, Polη 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 α3 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 Polη up-regulation, which contributes to mutagenesis and ultimately carcinogenesis in cells.
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Qi
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhu
authors.forename: Meng
authors.initials: M
authors.lastname: Lou
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Fan
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Lv
authors.forename: Jianzhen
authors.initials: J
authors.lastname: Shan
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhu
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.forename: Jimin
authors.initials: J
authors.lastname: Shao
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000650:Amnion / Q000166:cytology; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015386:Hazardous Substances / Q000633:toxicity; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D016296:Mutagenesis / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary; D015854:Up-Regulation / Q000502:physiology; D000099270:Y-Family DNA Polymerases
chemical_list: D002273:Carcinogens; D004259:DNA-Directed DNA Polymerase; D015386:Hazardous Substances; D050856:Interferon Regulatory Factor-1; D008769:Methylnitronitrosoguanidine; C494257:IRF1 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases