Cell Reports
Volume 13, Issue 10, 15 December 2015, Pages 2072-2080
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USP7 Is a Suppressor of PCNA Ubiquitination and Oxidative-Stress-Induced Mutagenesis in Human Cells

https://doi.org/10.1016/j.celrep.2015.11.014Get rights and content
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Highlights

  • USP7 deubiquitinates mono-ubiquitinated PCNA in vitro

  • USP7 suppresses UV- and oxidative-stress-induced PCNA mono-ubiquitination in cells

  • USP1 acts in S-phase, whereas USP7 acts throughout interphase

  • USP1 and USP7 suppress UV- and H2O2-induced mutagenesis, respectively

Summary

Mono-ubiquitinated PCNA activates error-prone DNA polymerases; therefore, strict regulation of PCNA mono-ubiquitination is crucial in avoiding undesired mutagenesis. In this study, we used an in vitro assay system to identify USP7 as a deubiquitinating enzyme of mono-ubiquitinated PCNA. Suppression of USP1, a previously identified PCNA deubiquitinase, or USP7 increased UV- and H2O2-induced PCNA mono-ubiquitination in a distinct and additive manner, suggesting that USP1 and USP7 make different contributions to PCNA deubiquitination in human cells. Cell-cycle-synchronization analyses revealed that USP7 suppression increased H2O2-induced PCNA ubiquitination throughout interphase, whereas USP1 suppression specifically increased ubiquitination in S-phase cells. UV-induced mutagenesis was elevated in USP1-suppressed cells, whereas H2O2-induced mutagenesis was elevated in USP7-suppressed cells. These results suggest that USP1 suppresses UV-induced mutations produced in a manner involving DNA replication, whereas USP7 suppresses H2O2-induced mutagenesis involving cell-cycle-independent processes such as DNA repair.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

4

Present address: Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo 125-8585, Japan

5

Co-first author