USP11 suppresses CHK1 activation by deubiquitinating CLASPIN

Hongchang Zhao; Zhifeng Wang; Min Zhu; Ji Liao; Xingzhi Xu

doi:10.1007/s42764-021-00034-1

Genome Instability & Disease ›› 2021, Vol. 2 ›› Issue (3) : 184-194. DOI: 10.1007/s42764-021-00034-1

Original Research Paper

USP11 suppresses CHK1 activation by deubiquitinating CLASPIN

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Abstract

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.

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Hongchang Zhao, Zhifeng Wang, Min Zhu, Ji Liao, Xingzhi Xu. USP11 suppresses CHK1 activation by deubiquitinating CLASPIN. Genome Instability & Disease, 2021, 2(3): 184‒194 https://doi.org/10.1007/s42764-021-00034-1

Funding

National Natural Science Foundation of China(31761133012); National Basic Research Program of China (973 Program)(2017YFA0503900); Science and Technology Planning Project of Shenzhen Municipality(JCYJ20170412113009742); Young Scientists Fund(32000911)