Abstract
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.
Highlights
Cells utilize DNA repair pathways to efficiently correct the deleterious effects of DNA damage
Results c-Jun is a critical transcriptional factor for POLI gene Considering the experimental clues showed that altered expression of pol i may be associated to hypermutagenesis and carcinogenesis, we firstly clarify its transcriptional regulation mechanism
We prove that activation of c-Jun directly enhances the basal and DNA damage induced expressions of pol i in normal cells and bladder cancer cells
Summary
Cells utilize DNA repair pathways to efficiently correct the deleterious effects of DNA damage. In some cases, not all damage can be repaired promptly and availably, which induces cell cycle arrest. To overcome this blockade to continue synthesis of the growing DNA chain, cells employ the molecular mechanisms that enable translesion DNA synthesis (TLS) to occur [1], [2]. As far as the error-prone DNA replication features of pol i, dysregulation of pol i may contribute to the acquisition of mutator phenotype that, along with defective cell cycle control or others genome stability pathways, could facilitate to accelerate the tumor progression. We previously first discovered that breast cancer cells overexpress pol i protein, which leads to UV-induced hypermutagenesis [4]. It is important to make our efforts to clarify the mechanism of regulation and to determine the carcinogenesis role of pol i in vivo
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