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

Swagata Halder, Ignacio Torrecilla, Martin D. Burkhalter, Marta Popović, John Fielden, Bruno Vaz, Judith Oehler, Domenic Pilger, Davor Lessel, Katherine Wiseman, Abhay Narayan Singh, Iolanda Vendrell, Roman Fischer, Melanie Philipp and Kristijan Ramadan ()
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Swagata Halder: University of Oxford
Ignacio Torrecilla: University of Oxford
Martin D. Burkhalter: Ulm University
Marta Popović: University of Oxford
John Fielden: University of Oxford
Bruno Vaz: University of Oxford
Judith Oehler: University of Oxford
Domenic Pilger: University of Oxford
Davor Lessel: University Medical Center Hamburg-Eppendorf
Katherine Wiseman: University of Oxford
Abhay Narayan Singh: University of Oxford
Iolanda Vendrell: University of Oxford
Roman Fischer: University of Oxford
Melanie Philipp: Ulm University
Kristijan Ramadan: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11095-y

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