The cullin-RING E3 ubiquitin ligase CRL4Cdt2 has emerged as a master regulator of genome stability, which targets key cell cycle proteins for proteolysis during S phase and after DNA damage. Recent advances shed light on how it couples ubiquitination to DNA synthesis, offering a new paradigm for substrate recognition: Cdt2 binds directly onto proliferating cell nuclear antigen (PCNA) loaded on DNA, which serves as a landing pad for the independent recruitment of the ubiquitin ligase and its substrates. Cyclin-dependent kinases (CDKs) and the ataxia telangiectasia and Rad3-related (ATR) kinase ensure accurate spatiotemporal regulation of CRL4Cdt2 under normal conditions and upon DNA damage. Deregulation of Cdt2 is evident in malignancies and was recently highlighted as a major target of oncogenic viruses, supporting the therapeutic targeting of the ligase as a promising anticancer strategy.

中文翻译：

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CRL4Cdt2：将基因组稳定性与泛素化相关联。

cullin-ring E3泛素连接酶CRL4Cdt2已成为基因组稳定性的主要调节剂，其靶向关键细胞周期蛋白以在S期和DNA损伤后进行蛋白水解。最近的进展揭示了其如何将泛素化与DNA合成相结合，为底物识别提供了新的范例：Cdt2直接结合到负载在DNA上的增殖细胞核抗原（PCNA）上，后者是泛素连接酶独立募集的平台。及其基材。细胞周期蛋白依赖性激酶（CDK）以及共济失调毛细血管扩张和Rad3相关（ATR）激酶可确保在正常条件下和DNA损伤后CRL4Cdt2的准确时空调节。Cdt2的异常表达在恶性肿瘤中很明显，并且最近被强调为致癌病毒的主要目标，