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SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
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Journal Article
SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
2019
Overview
The SPRTN metalloprotease is essential for DNA-protein crosslink (DPC) repair and DNA replication in vertebrate cells. Cells deficient in SPRTN protease exhibit DPC-induced replication stress and genome instability, manifesting as premature ageing and liver cancer. Here, we provide a body of evidence suggesting that SPRTN activates the ATR-CHK1 phosphorylation signalling cascade during physiological DNA replication by proteolysis-dependent eviction of CHK1 from replicative chromatin. During this process, SPRTN proteolyses the C-terminal/inhibitory part of CHK1, liberating N-terminal CHK1 kinase active fragments. Simultaneously, CHK1 full length and its N-terminal fragments phosphorylate SPRTN at the C-terminal regulatory domain, which stimulates SPRTN recruitment to chromatin to promote unperturbed DNA replication fork progression and DPC repair. Our data suggest that a SPRTN-CHK1 cross-activation loop plays a part in DNA replication and protection from DNA replication stress. Finally, our results with purified components of this pathway further support the proposed model of a SPRTN-CHK1 cross-activation loop.
Cells deficient in SPRTN protease activity exhibit severe DNA-protein crosslink induced replication stress and genome instability. Here the author reveal a functional link between the SPRTN protease and the CHK1 kinase during physiological DNA replication.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/31
/ 13/44
/ 13/51
/ 14
/ 14/1
/ 42
/ 42/70
/ 42/89
/ 64
/ 64/116
/ 82/83
/ Aging
/ Animals
/ Checkpoint Kinase 1 - metabolism
/ Checkpoint Kinase 1 - physiology
/ DNA
/ DNA-Binding Proteins - metabolism
/ DNA-Binding Proteins - physiology
/ Genomes
/ Humanities and Social Sciences
/ Kinases
/ Protease
/ Repair
/ Science
