The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis.
The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis.
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DOI：
10.1093/nar/gkw024
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发表时间：
2016-04-20
影响因子：
14.9
通讯作者：
Krejci L
中科院分区：
文献类型：
--
作者：
Burkovics P;Dome L;Juhasz S;Altmannova V;Sebesta M;Pacesa M;Fugger K;Sorensen CS;Lee MY;Haracska L;Krejci L
含损伤DNA复制的成功和准确完成主要需要重组和依赖于RAD18的DNA损伤耐受途径。RAD18至少控制两种不同的机制：跨损伤合成（TLS）和模板转换（TS）依赖性途径。虽然TS主要是无错误的，但TLS可以以易出错的方式工作，因此，这些途径的调节需要严格控制以防止DNA错误和潜在的致癌转化和肿瘤发生。在人类中，PCNA相关重组抑制剂（PARI）蛋白最近已显示出抑制同源重组（HR）事件。在这里，我们描述了一种生化机制，其中PARI作为HR调节器的功能后，复制叉停滞和双链断裂修复。在我们重建的生化系统中，我们发现PARI以PCNA相互作用依赖的方式抑制重组事件期间的DNA修复合成，但独立于其UvrD样解旋酶结构域。因此，我们证明PARI在体内抑制HR，并且其敲低抑制RAD18耗尽细胞的UV敏感性。我们的数据揭示了一种新的人类调节机制，限制了HR的程度，并代表了抗癌治疗的一个新的潜在靶点。
Successful and accurate completion of the replication of damage-containing DNA requires mainly recombination and RAD18-dependent DNA damage tolerance pathways. RAD18 governs at least two distinct mechanisms: translesion synthesis (TLS) and template switching (TS)-dependent pathways. Whereas TS is mainly error-free, TLS can work in an error-prone manner and, as such, the regulation of these pathways requires tight control to prevent DNA errors and potentially oncogenic transformation and tumorigenesis. In humans, the PCNA-associated recombination inhibitor (PARI) protein has recently been shown to inhibit homologous recombination (HR) events. Here, we describe a biochemical mechanism in which PARI functions as an HR regulator after replication fork stalling and during double-strand break repair. In our reconstituted biochemical system, we show that PARI inhibits DNA repair synthesis during recombination events in a PCNA interaction-dependent way but independently of its UvrD-like helicase domain. In accordance, we demonstrate that PARI inhibits HR in vivo, and its knockdown suppresses the UV sensitivity of RAD18-depleted cells. Our data reveal a novel human regulatory mechanism that limits the extent of HR and represents a new potential target for anticancer therapy.