SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
Standard
SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication. / 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.
In: NAT COMMUN, Vol. 10, No. 1, 17.07.2019, p. 3142.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication
AU - Halder, Swagata
AU - Torrecilla, Ignacio
AU - Burkhalter, Martin D
AU - Popović, Marta
AU - Fielden, John
AU - Vaz, Bruno
AU - Oehler, Judith
AU - Pilger, Domenic
AU - Lessel, Davor
AU - Wiseman, Katherine
AU - Singh, Abhay Narayan
AU - Vendrell, Iolanda
AU - Fischer, Roman
AU - Philipp, Melanie
AU - Ramadan, Kristijan
PY - 2019/7/17
Y1 - 2019/7/17
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-019-11095-y
DO - 10.1038/s41467-019-11095-y
M3 - SCORING: Journal article
C2 - 31316063
VL - 10
SP - 3142
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -