Overexpressed DNA polymerase iota regulated by JNK/c-Jun contributes to hypermutagenesis in bladder cancer

PLoS One. 2013 Jul 26;8(7):e69317. doi: 10.1371/journal.pone.0069317. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Cell Line, Tumor
  • DNA Polymerase iota
  • DNA-Binding Proteins / metabolism
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Molecular Sequence Data
  • Mutagenesis / genetics*
  • Mutation Rate
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Ultraviolet Rays
  • Urinary Bladder Neoplasms / enzymology*
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / pathology
  • Urothelium / pathology
  • Urothelium / radiation effects


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins c-jun
  • XPC protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • JNK Mitogen-Activated Protein Kinases
  • DNA-Directed DNA Polymerase
  • DNA Polymerase iota
  • POLI protein, human

Grants and funding

This work was supported by the National Nature Science Foundation of China (30770460) and Army Nature Science Foundation of China (06H026). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.