Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer.
Human DNA polymerase iota (pol ι) possesses high error-prone DNA replication features and performs translesion DNA synthesis. It may be specialized and strictly regulated in normal mammalian cells. Dysregulation of pol ι may contribute to the acquisition of a mutator phenotype. However, there are few reports describing the transcription regulatory mechanism of pol ι, and there is controversy regarding its role in carcinogenesis. In this study, we performed the deletion and point-mutation experiment, EMSA, ChIP, RNA interference and western blot assay to prove that c-Jun activated by c-Jun N-terminal kinase (JNK) regulates the transcription of pol ι in normal and cancer cells. Xeroderma pigmentosum group C protein (XPC) and ataxia-telangiectasia mutated related protein (ATR) promote early JNK activation in response to DNA damage and consequently enhance the expression of pol ι, indicating that the novel role of JNK signal pathway is involved in DNA damage response. Furthermore, associated with elevated c-Jun activity, the overexpression of pol ι is positively correlated with the clinical tumor grade in 97 bladder cancer samples and may contribute to the hypermutagenesis. The overexpressed pol ι-involved mutagenesis is dependent on JNK/c-Jun pathway in bladder cancer cells identifying by the special mutation spectra. Our results support the conclusion that dysregulation of pol ι by JNK/c-Jun is involved in carcinogenesis and offer a novel understanding of the role of pol ι or c-Jun in mutagenesis.
Urology Institute of People Liberation Army, Southwest Hospital, The Third Military Medical University, Chongqing, China.
Fang
F
Yuan
Zhigang
Z
Xu
Mingzhen
M
Yang
Quanfang
Q
Wei
Yi
Y
Zhang
Jin
J
Yu
Yi
Y
Zhi
Yang
Y
Liu
Zhiwen
Z
Chen
Jin
J
Yang
D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D059645:Mutation Rate; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D014466:Ultraviolet Rays; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000473:pathology / Q000528:radiation effects; D000094769:DNA Polymerase iota
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; C086984:XPC protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D004259:DNA-Directed DNA Polymerase; D000094769:DNA Polymerase iota; C000722070:POLI protein, human