title: SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks.
abstract: Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in theSPRTNgene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome developed hepatocellular carcinoma. Here we describe the molecular mechanism by which SPRTN contributes to genome stability and normal cellular homeostasis. We show that SPRTN is a DNA-dependent mammalian protease required for resolving cytotoxic DNA-protein crosslinks (DPCs)- a function that had only been attributed to the metalloprotease Wss1 in budding yeast. We provide genetic evidence that SPRTN and Wss1 function distinctly in vivo to resolve DPCs. Upon DNA and ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates and itself.SPRTNnull cells or cells derived from patients with Ruijs-Aalfs syndrome are impaired in the resolution of covalent DPCs in vivo. Collectively, SPRTN is a mammalian protease required for resolving DNA-protein crosslinks in vivo whose function is compromised in Ruijs-Aalfs syndrome patients.
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.
authors.forename: Jaime
authors.identifier: 0000-0003-0301-1971
authors.initials: J
authors.lastname: Lopez-Mosqueda
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.|Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
authors.forename: Karthik
authors.initials: K
authors.lastname: Maddi
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prgomet
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.|Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
authors.forename: Sissy
authors.initials: S
authors.lastname: Kalayil
authors.affiliation: Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Marinovic-Terzic
authors.affiliation: Department of Immunology and Medical Genetics, University of Split, School of Medicine, Split, Croatia.
authors.forename: Janos
authors.initials: J
authors.lastname: Terzic
authors.affiliation: Institute of Biochemistry II, Goethe University School of Medicine, Frankfurt, Germany.|Buchmann Institute for Molecular Life Sciences, Goethe University, Frankfurt, Germany.
authors.forename: Ivan
authors.identifier: 0000-0001-8156-9511
authors.initials: I
authors.lastname: Dikic
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008322:Mammals; D009154:Mutation; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C574636:SPRTN protein, human; D029701:Saccharomyces cerevisiae Proteins; C494617:WSS1 protein, S cerevisiae
keywords: DNA replication; DNA-protein crosslinks; Dvc1; E. coli; Ruijs-Aalfs syndrome; S. cerevisiae; SPARTAN; SPRTN; Topoisomerase; aging; biochemistry; c1orf124; cell biology; human; metalloprotease; mouse; progeria; ubiquitination