PUBLICATION
SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
- Authors
- Halder, S., Torrecilla, I., Burkhalter, M.D., Popović, M., Fielden, J., Vaz, B., Oehler, J., Pilger, D., Lessel, D., Wiseman, K., Singh, A.N., Vendrell, I., Fischer, R., Philipp, M., Ramadan, K.
- ID
- ZDB-PUB-191226-35
- Date
- 2019
- Source
- Nature communications 10: 3142 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Checkpoint Kinase 1/metabolism
- Checkpoint Kinase 1/physiology*
- DNA Breaks
- DNA Replication
- DNA-Binding Proteins/metabolism
- DNA-Binding Proteins/physiology*
- Genomic Instability
- Models, Genetic*
- Phosphorylation
- Signal Transduction
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 31316063 Full text @ Nat. Commun.
Citation
Halder, S., Torrecilla, I., Burkhalter, M.D., Popović, M., Fielden, J., Vaz, B., Oehler, J., Pilger, D., Lessel, D., Wiseman, K., Singh, A.N., Vendrell, I., Fischer, R., Philipp, M., Ramadan, K. (2019) SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication. Nature communications. 10:3142.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping