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.
- Authors:
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC)
- OSTI Identifier:
- 1402386
- Alternate Identifier(s):
- OSTI ID: 1379586
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Published Article
- Journal Name:
- Molecular Cell
- Additional Journal Information:
- Journal Name: Molecular Cell Journal Volume: 64 Journal Issue: 4; Journal ID: ISSN 1097-2765
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; DNA-protein crosslinks; DNA repair; DVC1; formaldehyde; hepatocellular carcinoma; progeria; protease Ruijs-Aalfs syndrome; SPRTN; Spartan; topoisomerase; Wss1
Citation Formats
Stingele, Julian, Bellelli, Roberto, Alte, Ferdinand, Hewitt, Graeme, Sarek, Grzegorz, Maslen, Sarah L., Tsutakawa, Susan E., Borg, Annabel, Kjær, Svend, Tainer, John A., Skehel, J. Mark, Groll, Michael, and Boulton, Simon J. Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN. United States: N. p., 2016.
Web. doi:10.1016/j.molcel.2016.09.031.
Stingele, Julian, Bellelli, Roberto, Alte, Ferdinand, Hewitt, Graeme, Sarek, Grzegorz, Maslen, Sarah L., Tsutakawa, Susan E., Borg, Annabel, Kjær, Svend, Tainer, John A., Skehel, J. Mark, Groll, Michael, & Boulton, Simon J. Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN. United States. https://doi.org/10.1016/j.molcel.2016.09.031
Stingele, Julian, Bellelli, Roberto, Alte, Ferdinand, Hewitt, Graeme, Sarek, Grzegorz, Maslen, Sarah L., Tsutakawa, Susan E., Borg, Annabel, Kjær, Svend, Tainer, John A., Skehel, J. Mark, Groll, Michael, and Boulton, Simon J. Tue .
"Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN". United States. https://doi.org/10.1016/j.molcel.2016.09.031.
@article{osti_1402386,
title = {Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN},
author = {Stingele, Julian and Bellelli, Roberto and Alte, Ferdinand and Hewitt, Graeme and Sarek, Grzegorz and Maslen, Sarah L. and Tsutakawa, Susan E. and Borg, Annabel and Kjær, Svend and Tainer, John A. and Skehel, J. Mark and Groll, Michael and Boulton, Simon J.},
abstractNote = {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.},
doi = {10.1016/j.molcel.2016.09.031},
journal = {Molecular Cell},
number = 4,
volume = 64,
place = {United States},
year = {Tue Nov 01 00:00:00 EDT 2016},
month = {Tue Nov 01 00:00:00 EDT 2016}
}
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https://doi.org/10.1016/j.molcel.2016.09.031
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Works referencing / citing this record:
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