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.
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vaz
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Popovic
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Newman
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Fielden
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Hazel
authors.initials: H
authors.lastname: Aitkenhead
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Swagata
authors.initials: S
authors.lastname: Halder
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Abhay Narayan
authors.initials: AN
authors.lastname: Singh
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Vendrell
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torrecilla
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Neele
authors.initials: N
authors.lastname: Drobnitzky
authors.affiliation: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, Ofra s/n, 38320 La Laguna, Tenerife, Spain.
authors.forename: Raimundo
authors.initials: R
authors.lastname: Freire
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.affiliation: TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Gillies W
authors.initials: GW
authors.lastname: McKenna
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.affiliation: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: kristijan.ramadan@oncology.ox.ac.uk.
authors.forename: Kristijan
authors.initials: K
authors.lastname: Ramadan
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005047:Etoposide / Q000737:chemistry; D005557:Formaldehyde / Q000737:chemistry; D015870:Gene Expression; D042822:Genomic Instability; D006801:Humans; D007700:Kinetics; D009154:Mutation; D011485:Protein Binding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013577:Syndrome; D014466:Ultraviolet Rays
chemical_list: D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C574636:SPRTN protein, human; D005557:Formaldehyde; D005047:Etoposide; D004247:DNA
keywords: DNA replication; DNA-dependent metalloprotease; DNA-protein crosslink repair; Ruijs-Aalfs/SPARTAN syndrome; SPARTAN/DVC1; aging; cancer