期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 31, 期 16, 页码 3396-3409出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.05117-11
关键词
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资金
- Ministry of Education, Science, Technology, Sports and Culture of Japan
- Ministry of Health, Labor and Welfare of Japan
- Grants-in-Aid for Scientific Research [23501257, 22790306, 22131008, 22131001, 23131503, 22249005, 22590264] Funding Source: KAKEN
REV1 is a Y-family polymerase that plays a central role in mutagenic translesion DNA synthesis (TLS), contributing to tumor initiation and progression. In a current model, a monoubiquitinated form of the replication accessory protein, proliferating cell nuclear antigen (PCNA), serves as a platform to recruit REV1 to damaged sites on the DNA template. Emerging evidence indicates that posttranslational mechanisms regulate REV1 in yeast; however, the regulation of REV1 in higher eukaryotes is poorly understood. Here we show that the molecular chaperone Hsp90 is a critical regulator of REV1 in human cells. Hsp90 specifically binds REV1 in vivo and in vitro. Treatment with a specific inhibitor of Hsp90 reduces REV1 protein levels in several cell types through proteasomal degradation. This is associated with suppression of UV-induced mutagenesis. Furthermore, Hsp90 inhibition disrupts the interaction between REV1 and monoubiquitinated PCNA and suppresses UV-induced focus formation. These results indicate that Hsp90 promotes folding of REV1 into a stable and/or functional form(s) to bind to monoubiquitinated PCNA. The present findings reveal a novel role of Hsp90 in the regulation of TLS-mediated mutagenesis.
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