@article{7ada5e5917b0495ba12a6fc5e4ec0308,
title = "Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN",
abstract = "Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTN accomplishes DPC processing through a unique DNA-induced protease activity, which is controlled by several sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNA switch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, and regulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTN deficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.",
keywords = "DNA repair, DNA-protein crosslinks, DVC1, formaldehyde, hepatocellular carcinoma, progeria, protease, Ruijs-Aalfs syndrome, Spartan, SPRTN, topoisomerase, Wss1",
author = "Julian Stingele and Roberto Bellelli and Ferdinand Alte and Graeme Hewitt and Grzegorz Sarek and Maslen, {Sarah L.} and Tsutakawa, {Susan E.} and Annabel Borg and Svend Kj{\ae}r and Tainer, {John A.} and Skehel, {J. Mark} and Michael Groll and Boulton, {Simon J.}",
note = "Funding Information: We thank Yuichi Machida for providing Sprtn − MEFs; John Rouse for anti-SPRTN polyclonal antibody; Bjoern Schumacher, Anton Gartner, and the Caenorhabditis Genetics Center for C. elegans strains; Vesela Encheva and Bram Snijders for mass spectrometry analysis; the staff of the macromolecular crystallography beamline X06SA (PXI) of the Paul Scherrer Institute, Swiss Light Source, for help with data collection; Stefan Jentsch for discussions and support; and members of the S.J.B. laboratory for comments and discussion throughout the project. SAXS data were collected at the SIBYLS beamline 12.3.1 at the Advanced Light Source (ALS) at Lawrence Berkeley National Laboratory, supported by the Department of Energy (DOE, IDAT program) and the National Cancer Institute ( NCI , PO1CA92584 ). J.A.T. is supported by the Cancer Prevention and Research Institute of Texas and a Robert A. Welch Chemistry Chair. J.S. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship (ALTF 470-2015), and G.S. is supported by an EMBO advanced fellowship (ALTF 1656-2014). This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK ( FC0010048 ), the UK Medical Research Council ( FC0010048 ), and the Wellcome Trust ( FC0010048 ); a European Research Council (ERC) Advanced Investigator Grant (RecMitMei); and a Wellcome Trust Senior Investigator Grant. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = nov,
day = "17",
doi = "10.1016/j.molcel.2016.09.031",
language = "English",
volume = "64",
pages = "688--703",
journal = "MOLECULAR CELL",
issn = "1097-2765",
publisher = "Cell Press",
number = "4",
}
