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

Vaz, Bruno; Popović, Marta; Newman, Joseph A.; Fielden, John; Aitkenhead, Hazel; Halder, Swagata; Singh, Abhay Narayan; Ramadan, Kristijan (2016) Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Molecular Cell, 64 (4). pp. 704-719. ISSN 1097-2765

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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.

Item Type: Article
Uncontrolled Keywords: DNA replication ; DNA-dependent metalloprotease ; DNA-protein crosslink repair ; Ruijs-Aalfs/SPARTAN syndrome ; SPARTAN/DVC1 ; aging ; cancer
Subjects: NATURAL SCIENCES > Biology
NATURAL SCIENCES > Biology > Biochemistry and Molecular Biology
Divisions: Division for Marine and Enviromental Research
Depositing User: Marta Popović
Date Deposited: 07 Nov 2018 16:25
DOI: 10.1016/j.molcel.2016.09.032

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