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; Kristijan Ramadan

doi:10.1038/s41467-019-11095-y

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, Kristijan Ramadan^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

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.

Original language	English
Article number	3142
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11095-y
Publication status	Published - Dec 1 2019
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-11095-y

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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(1), Article 3142. https://doi.org/10.1038/s41467-019-11095-y

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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.",

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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

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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.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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