SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication

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 evidenc...

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Vydáno v:	Nature communications Ročník 10; číslo 1; s. 3142 - 18
Hlavní autoři:	Halder, Swagata, Torrecilla, Ignacio, Burkhalter, Martin D., Popović, Marta, Fielden, John, Vaz, Bruno, Oehler, Judith, Pilger, Domenic, Lessel, Davor, Wiseman, Katherine, Singh, Abhay Narayan, Vendrell, Iolanda, Fischer, Roman, Philipp, Melanie, Ramadan, Kristijan
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 17.07.2019 Nature Publishing Group Nature Portfolio
Témata:	13 13/106 13/31 13/44 13/51 14 14/1 42 42/70 42/89 631/337/151/2353 631/80/474 64 64/116 82/83 Activation Aging Animals Checkpoint Kinase 1 - metabolism Checkpoint Kinase 1 - physiology CHK1 protein Chromatin Crosslinking Deoxyribonucleic acid DNA DNA biosynthesis DNA Breaks DNA repair DNA Replication DNA-Binding Proteins - metabolism DNA-Binding Proteins - physiology Fragments Genomes Genomic Instability Humanities and Social Sciences Kinases Liver cancer Metalloproteinase Models, Genetic multidisciplinary Phosphorylation Protease Proteolysis Repair Replication Science Science (multidisciplinary) Signal Transduction Stability Vertebrates Zebrafish - genetics Zebrafish - metabolism
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-11095-y