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USP7 Is a Suppressor of PCNA Ubiquitination and Oxidative-Stress-Induced Mutagenesis in Human Cells

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...

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Published in:Cell reports (Cambridge) 2015-12, Vol.13 (10), p.2072-2080
Main Authors: Kashiwaba, Shu-ichiro, Kanao, Rie, Masuda, Yuji, Kusumoto-Matsuo, Rika, Hanaoka, Fumio, Masutani, Chikahide
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Language:English
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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. [Display omitted] •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 PCNA mono-ubiquitination regulation is crucial for a balance of DNA damage tolerance and mutagenesis. Kashiwaba et al. reveal that USP7 deubiquitinates mono-ubiquitinated PCNA. Different from USP1, which suppresses DNA-replication-coupled PCNA ubiquitination and mutagenesis after UV irradiation, USP7 suppresses oxidative-stress-induced PCNA ubiquitination and mutagenesis independently of the cell cycle.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2015.11.014