Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

Bruno Vaz; Marta Popovic; Joseph A. Newman; John Fielden; Hazel Aitkenhead; Swagata Halder; Abhay Narayan Singh; Iolanda Vendrell; Roman Fischer; Ignacio Torrecilla; Neele Drobnitzky; Raimundo Freire; David J. Amor; Paul J. Lockhart; Benedikt M. Kessler; Gillies W. McKenna; Opher Gileadi; Kristijan Ramadan

doi:10.1016/j.molcel.2016.09.032

Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

Bruno Vaz, Marta Popovic, Joseph A. Newman, John Fielden, Hazel Aitkenhead, Swagata Halder, Abhay Narayan Singh, Iolanda Vendrell, Roman Fischer, Ignacio Torrecilla, Neele Drobnitzky, Raimundo Freire, David J. Amor, Paul J. Lockhart, Benedikt M. Kessler, Gillies W. McKenna, Opher Gileadi, Kristijan Ramadan^*

^*Corresponding author for this work

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

192 Citations (Scopus)

Abstract

The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.

Original language	English
Pages (from-to)	704-719
Number of pages	16
Journal	Molecular Cell
Volume	64
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2016.09.032
Publication status	Published - Nov 17 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 The Authors

ASJC Scopus Subject Areas

Molecular Biology
Cell Biology

Keywords

aging
cancer
DNA replication
DNA-dependent metalloprotease
DNA-protein crosslink repair
Ruijs-Aalfs/SPARTAN syndrome
SPARTAN/DVC1

UN SDGs

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

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10.1016/j.molcel.2016.09.032

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Vaz, B., Popovic, M., Newman, J. A., Fielden, J., Aitkenhead, H., Halder, S., Singh, A. N., Vendrell, I., Fischer, R., Torrecilla, I., Drobnitzky, N., Freire, R., Amor, D. J., Lockhart, P. J., Kessler, B. M., McKenna, G. W., Gileadi, O., & Ramadan, K. (2016). Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular Cell, 64(4), 704-719. https://doi.org/10.1016/j.molcel.2016.09.032

@article{eb52a83438b2415d89fb015ead01d191,

title = "Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair",

abstract = "The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.",

keywords = "aging, cancer, DNA replication, DNA-dependent metalloprotease, DNA-protein crosslink repair, Ruijs-Aalfs/SPARTAN syndrome, SPARTAN/DVC1",

author = "Bruno Vaz and Marta Popovic and Newman, {Joseph A.} and John Fielden and Hazel Aitkenhead and Swagata Halder and Singh, {Abhay Narayan} and Iolanda Vendrell and Roman Fischer and Ignacio Torrecilla and Neele Drobnitzky and Raimundo Freire and Amor, {David J.} and Lockhart, {Paul J.} and Kessler, {Benedikt M.} and McKenna, {Gillies W.} and Opher Gileadi and Kristijan Ramadan",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = nov,

day = "17",

doi = "10.1016/j.molcel.2016.09.032",

language = "English",

volume = "64",

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Vaz, B, Popovic, M, Newman, JA, Fielden, J, Aitkenhead, H, Halder, S, Singh, AN, Vendrell, I, Fischer, R, Torrecilla, I, Drobnitzky, N, Freire, R, Amor, DJ, Lockhart, PJ, Kessler, BM, McKenna, GW, Gileadi, O & Ramadan, K 2016, 'Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair', Molecular Cell, vol. 64, no. 4, pp. 704-719. https://doi.org/10.1016/j.molcel.2016.09.032

TY - JOUR

T1 - Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

AU - Vaz, Bruno

AU - Popovic, Marta

AU - Newman, Joseph A.

AU - Fielden, John

AU - Aitkenhead, Hazel

AU - Halder, Swagata

AU - Singh, Abhay Narayan

AU - Vendrell, Iolanda

AU - Fischer, Roman

AU - Torrecilla, Ignacio

AU - Drobnitzky, Neele

AU - Freire, Raimundo

AU - Amor, David J.

AU - Lockhart, Paul J.

AU - Kessler, Benedikt M.

AU - McKenna, Gillies W.

AU - Gileadi, Opher

AU - Ramadan, Kristijan

PY - 2016/11/17

Y1 - 2016/11/17

N2 - The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.

AB - The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.

KW - aging

KW - cancer

KW - DNA replication

KW - DNA-dependent metalloprotease

KW - DNA-protein crosslink repair

KW - Ruijs-Aalfs/SPARTAN syndrome

KW - SPARTAN/DVC1

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U2 - 10.1016/j.molcel.2016.09.032

DO - 10.1016/j.molcel.2016.09.032

M3 - Article

C2 - 27871366

AN - SCOPUS:84995602245

SN - 1097-2765

VL - 64

SP - 704

EP - 719

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

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