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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 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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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.
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•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. |
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ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2015.11.014 |