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...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications Vol. 10; no. 1; pp. 3142 - 18
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 17.07.2019
Nature Publishing Group
Nature Portfolio
Subjects:
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
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography: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