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 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.
Author: | Jaime Lopez-Mosqueda, Karthik Maddi, Stefan Prgomet, Sissy Kalayil, Ivana Marinovic-Terzic, Janos Terzic, Ivan ĐikićORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-421583 |
DOI: | https://doi.org/10.7554/eLife.21491 |
ISSN: | 2050-084X |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/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 |
Page Number: | 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 / Medizin |
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe | |
Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung 4.0 |