2. Academic Validation
  3. Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair

  • Mol Cell. 2016 Nov 17;64(4):704-719. doi: 10.1016/j.molcel.2016.09.032.
Bruno Vaz 1,  Marta Popovic 1,  Joseph A Newman 2,  John Fielden 1,  Hazel Aitkenhead 2,  Swagata Halder 1,  Abhay Narayan Singh 1,  Iolanda Vendrell 3,  Roman Fischer 4,  Ignacio Torrecilla 1,  Neele Drobnitzky 1,  Raimundo Freire 5,  David J Amor 6,  Paul J Lockhart 6,  Benedikt M Kessler 4,  Gillies W McKenna 1,  Opher Gileadi 2,  Kristijan Ramadan 7
Affiliations

Affiliations

  • 1 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • 2 Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
  • 3 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 4 TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 5 Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas, Ofra s/n, 38320 La Laguna, Tenerife, Spain.
  • 6 Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.
  • 7 Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: [email protected].
PMID: 27871366 DOI: 10.1016/j.molcel.2016.09.032
Abstract

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 DPC-inducing 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.

Keywords

DNA replication; DNA-dependent metalloprotease; DNA-protein crosslink repair; Ruijs-Aalfs/SPARTAN syndrome; SPARTAN/DVC1; aging; cancer.

Figures