Molecular Chaperone Hsp90 Regulates REV1-Mediated Mutagenesis
Molecular Chaperone Hsp90 Regulates REV1-Mediated Mutagenesis
复制标题
DOI：
10.1128/mcb.05117-11
复制
发表时间：
2011-08-01
影响因子：
5.3
通讯作者：
Yamashita, Takayuki
中科院分区：
文献类型：
--
作者：
Pozo, Franklin Mayca;Oda, Tsukasa;Yamashita, Takayuki
REV1是一种y家族聚合酶，在致突变翻译DNA合成（TLS）中起核心作用，有助于肿瘤的发生和发展。在目前的模型中，复制辅助蛋白的单泛素化形式，增殖细胞核抗原（PCNA），作为一个平台，将REV1招募到DNA模板上的受损部位。新出现的证据表明，酵母的翻译后机制调节REV1；然而，REV1在高等真核生物中的调控作用尚不清楚。在这里，我们发现分子伴侣Hsp90是人类细胞中REV1的关键调节因子。Hsp90在体内和体外特异性结合REV1。Hsp90特异性抑制剂通过蛋白酶体降解降低几种细胞类型中的REV1蛋白水平。这与紫外线诱变的抑制有关。此外，Hsp90抑制破坏REV1与单泛素化PCNA之间的相互作用，抑制紫外线诱导的病灶形成。这些结果表明，Hsp90促进REV1折叠成稳定和/或功能形式，以结合单泛素化的PCNA。目前的研究结果揭示了Hsp90在调节tls介导的突变中的新作用。
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.