TY  - JOUR
A1  - Lopez-Mosqueda, Jaime
A1  - Maddi, Karthik
A1  - Prgomet, Stefan
A1  - Kalayil, Sissy
A1  - Marinovic-Terzic, Ivana
A1  - Terzic, Janos
A1  - Đikić, Ivan
T1  - SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks
T2  - Elife
N2  - 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.
KW  - DNA replication
KW  - DNA-protein crosslinks
KW  - Dvc1
KW  - E. coli
KW  - Ruijs-Aalfs syndrome
KW  - S. cerevisiae
KW  - SPARTAN
KW  - SPRTN
KW  - Topoisomerase
KW  - aging
KW  - biochemistry
KW  - c1orf124
KW  - cell biology
KW  - human
KW  - metalloprotease
KW  - mouse
KW  - progeria
KW  - ubiquitination
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/42158
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-421583
SN  - 2050-084X
N1  - 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.
VL  - 5
IS  - e21491
SP  - 1
EP  - 19
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -