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
  • 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.