SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 07 2019
17 07 2019
Historique:
received:
03
05
2019
accepted:
21
06
2019
entrez:
19
7
2019
pubmed:
19
7
2019
medline:
24
12
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31316063
doi: 10.1038/s41467-019-11095-y
pii: 10.1038/s41467-019-11095-y
pmc: PMC6637133
doi:
Substances chimiques
DNA-Binding Proteins
0
SPRTN protein, human
0
CHEK1 protein, human
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3142Subventions
Organisme : Medical Research Council
ID : MC_EX_MR/K022830/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00001/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M016587/1
Pays : United Kingdom
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