The DNA replication stress-induced checkpoint activated through the TopBP1-ATR axis is important for maintaining genomic stability. However, the regulation of TopBP1 in DNA-damage responses remains unclear. In this study, we identify the deubiquitinating enzyme (DUB) USP13 as an important regulator of TopBP1. Mechanistically, USP13 binds to TopBP1 and stabilizes TopBP1 by deubiquitination. Depletion of USP13 impedes ATR activation and hypersensitizes cells to replication stress-inducing agents. Furthermore, high USP13 expression enhances the replication stress response, promotes cancer cell chemoresistance, and is correlated with poor prognosis of cancer patients. Overall, these findings suggest that USP13 is a novel deubiquitinating enzyme for TopBP1 and coordinates the replication stress response.

通过 TopBP1-ATR 轴激活的 DNA 复制应激诱导的检查点对于维持基因组稳定性很重要。然而，TopBP1 在 DNA 损伤反应中的调节仍不清楚。在这项研究中，我们将去泛素化酶 (DUB) USP13 鉴定为 TopBP1 的重要调节因子。从机制上讲，USP13 与 TopBP1 结合并通过去泛素化稳定 TopBP1。USP13 的消耗会阻碍 ATR 激活并使细胞对复制应激诱导剂过敏。此外，USP13 的高表达增强了复制应激反应，促进了癌细胞的化学抗性，并与癌症患者的不良预后相关。总体而言，这些发现表明 USP13 是一种新型的 TopBP1 去泛素化酶，并协调复制应激反应。