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USP7 modulates UV-induced PCNA monoubiquitination by regulating DNA polymerase eta stability

Oncogene volume 34, pages 4791–4796 (2015)Cite this article

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Abstract

DNA polymerase eta (Polη) has unique and pivotal functions in several DNA damage-tolerance pathways. Steady-state level of this short-lived protein is tightly controlled by multiple mechanisms including proteolysis. Here, we have identified the deubiquitinating enzyme (DUB), ubiquitin-specific protease 7 (USP7), as a novel regulator of Polη stability. USP7 regulates Polη stability through both indirect and direct mechanisms. Knockout of USP7 increased the steady-state level of Polη and slowed down the turnover of both Polη and p53 proteins through destabilizing their E3 ligase murine double minute 2 (Mdm2). Also, USP7 physically binds Polη in vitro and in vivo. Overexpression of wild-type USP7 but not its catalytically-defective mutants deubiquitinates Polη and increases its cellular steady-state level. Thus, USP7 directly serves as a specific DUB for Polη. Furthermore, ectopic expression of USP7 promoted the UV-induced proliferating cell nuclear antigen (PCNA) monoubiquitination in Polη-proficient but not in Polη-deficient XPV (Xeroderma pigmentosum variant) cells, suggesting that USP7 facilitates UV-induced PCNA monoubiquitination by stabilizing Polη. Taken together, our findings reveal a modulatory role of USP7 in PCNA ubiquitination-mediated stress-tolerance pathways by fine-tuning Polη turnover.

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Acknowledgements

We are thankful to Dr Bert Vogelstein for HCT116, HCT116 p53−/− and HCT116 USP7−/− cells; Dr Alan Lehmann for XP30RO and XP30RO-GFP-Polη cells; Drs Yanhui Xu and Yang Shi for FLAG-tagged WT and CS USP7 constructs; Dr Carol Prives for Myc-Mdm2 construct. This work was supported by grants from the National Institutes of Health (ES012991 and ES023883) to AAW.

Author Contributions

JQ and AAW designed research; JQ, KP and AKS performed research; JQ, KP, QZ, QW, AKS, JH and AAW analyzed data; JQ and AAW wrote the manuscript.

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Authors and Affiliations

  1. Department of Radiology, The Ohio State University, Columbus, OH, USA

    J Qian, K Pentz, Q Zhu, Q Wang, J He, A K Srivastava & A A Wani

  2. Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA

    A A Wani

  3. James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH, USA

    A A Wani

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  1. J Qian
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  2. K Pentz
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  3. Q Zhu
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  4. Q Wang
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  5. J He
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  6. A K Srivastava
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  7. A A Wani
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Correspondence to J Qian or A A Wani.

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Qian, J., Pentz, K., Zhu, Q. et al. USP7 modulates UV-induced PCNA monoubiquitination by regulating DNA polymerase eta stability. Oncogene 34, 4791–4796 (2015). https://doi.org/10.1038/onc.2014.394

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  • DOI: https://doi.org/10.1038/onc.2014.394

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