Journal
MOLECULAR CELL
Volume 64, Issue 4, Pages 704-719Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.09.032
Keywords
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Categories
Funding
- Medical Research Council [MC_PC_12001/1]
- University of Oxford
- John Fell Fund [133/075]
- Wellcome Trust [097813/Z/11/Z, 106169/ZZ14/Z]
- Kennedy Trust
- NHMRC [GNT1032364]
- Victorian State Government
- Australian Government NHMRC IRIISS
- SGC - AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust [097813/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MC_PC_12001/1] Funding Source: UKRI
- Medical Research Council [MC_PC_12001/1] Funding Source: researchfish
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The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPCinducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.
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