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

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 charac...

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Published in:Molecular cell Vol. 64; no. 4; pp. 704 - 719
Main Authors: Vaz, Bruno, Popovic, Marta, Newman, Joseph A, Fielden, John, Aitkenhead, Hazel, Halder, Swagata, Singh, Abhay Narayan, Vendrell, Iolanda, Fischer, Roman, Torrecilla, Ignacio, Drobnitzky, Neele, Freire, Raimundo, Amor, David J, Lockhart, Paul J, Kessler, Benedikt M, McKenna, Gillies W, Gileadi, Opher, Ramadan, Kristijan
Format: Journal Article
Language:English
Published: United States 17.11.2016
Subjects:
Amino Acid Sequence
Binding Sites
Cross-Linking Reagents - chemistry
DNA - chemistry
DNA - genetics
DNA - metabolism
DNA Damage
DNA Repair
DNA Replication
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Etoposide - chemistry
Formaldehyde - chemistry
Gene Expression
Genomic Instability
Humans
Kinetics
Mutation
Protein Binding
Sequence Alignment
Sequence Homology, Amino Acid
Substrate Specificity
Syndrome
Ultraviolet Rays
DNA replication
DNA-protein crosslink repair
SPARTAN/DVC1
cancer
aging
DNA-dependent metalloprotease
Ruijs-Aalfs/SPARTAN syndrome
ISSN:1097-4164
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Summary: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.
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ISSN:1097-4164
DOI:10.1016/j.molcel.2016.09.032