USP11 suppresses CHK1 activation by deubiquitinating CLASPIN

CLASPIN is an essential mediator of ATR-dependent CHK1 activation in the DNA replication checkpoint. K6-linked polyubiquitination of CLASPIN promotes its chromatin loading and subsequent CHK1 activation. Here, we found that ubiquitin-specific protease 11 (USP11) deubiquitinates the K6-linkage polyubiquitinated form of CLASPIN. Under steady-state conditions, USP11 interacts with CLASPIN, reducing CLASPIN K6-linked ubiquitination levels. In response to replication stress, USP11 is phosphorylated by ATR and subsequently disassociated from CLASPIN, promoting CLASPIN chromatin loading, CHK1 activation and ultimately genome stability. Taken together, our findings uncover a novel function of USP11 in negatively regulating CHK1 activation by suppressing CLASPIN chromatin loading.