SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks

Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. Cells derived from patients with SPRTN mutations elicit genomic instability and people afflicted with this syndrome devel
Ruijs-Aalfs syndrome is a segmental progeroid syndrome resulting from mutations in the SPRTN gene. 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. SPRTN null 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.
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Metadaten
Author:Jaime Lopez-Mosqueda, Karthik Maddi, Stefan Prgomet, Sissy Kalayil, Ivana Marinovic-Terzic, Janos Terzic, Ivan Dikic
URN:urn:nbn:de:hebis:30:3-421583
DOI:http://dx.doi.org/10.7554/eLife.21491
ISSN:2050-084X
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=27852435
Parent Title (English):Elife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Contributor(s):Wade Harper
Document Type:Article
Language:English
Date of Publication (online):2016/12/01
Date of first Publication:2016/11/17
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/01
Tag: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
Volume:5
Issue:e21491
Pagenumber:19
First Page:1
Last Page:19
Note:
Copyright Lopez-Mosqueda et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
HeBIS PPN:424943719
Institutes:Medizin
Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:570 Biowissenschaften; Biologie
610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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