SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks
- Goethe University School of Medicine, Germany
- University of Split, Croatia
Abstract
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 persons 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 or ubiquitin binding, SPRTN can elicit proteolytic activity; cleaving DPC substrates or 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.
Article and author information
Author details
Jaime Lopez-Mosqueda
Funding
Deutsche Forschungsgemeinschaft (SFB1177)
- Ivan Dikic
Deutsche Forschungsgemeinschaft (CEF-MC)
- Ivan Dikic
Human Frontier Science Program (Postdoctoral fellowship)
- Jaime Lopez-Mosqueda
LOEWE Zentrum CGT and Loewe Network Ub Net (Fellowships)
- Ivan Dikic
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Lopez-Mosqueda et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks
eLife 5:e21491.
https://doi.org/10.7554/eLife.21491
