The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability

  • Cell Rep. 2021 Dec 7;37(10):110080. doi: 10.1016/j.celrep.2021.110080.
Annamaria Ruggiano  1 ,  Bruno Vaz  1 ,  Susan Kilgas  1 ,  Marta Popović  2 ,  Gonzalo Rodriguez-Berriguete  1 ,  Abhay N Singh  1 ,  Geoff S Higgins  1 ,  Anne E Kiltie  1 ,  Kristijan Ramadan  3
Affiliations
  • 1. Medical Research Council (MRC) Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
  • 2. Medical Research Council (MRC) Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK; Laboratory for Molecular Ecotoxicology, Division for Marine and Environmental Research, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
  • 3. Medical Research Council (MRC) Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK. Electronic address: [email protected].
PMID: 34879279 DOI: 10.1016/j.celrep.2021.110080
Abstract

DNA-protein crosslinks (DPCs) are a specific type of DNA lesion in which proteins are covalently attached to DNA. Unrepaired DPCs lead to genomic instability, Cancer, neurodegeneration, and accelerated aging. DPC proteolysis was recently identified as a specialized pathway for DPC repair. The DNA-dependent protease SPRTN and the 26S Proteasome emerged as two independent proteolytic systems. DPCs are also repaired by homologous recombination (HR), a canonical DNA repair pathway. While studying the cellular response to DPC formation, we identify ubiquitylation and SUMOylation as two major signaling events in DNA replication-coupled DPC repair. DPC ubiquitylation recruits SPRTN to repair sites, promoting DPC removal. DPC SUMOylation prevents DNA double-strand break formation, HR activation, and potentially deleterious genomic rearrangements. In this way, SUMOylation channels DPC repair toward SPRTN proteolysis, which is a safer pathway choice for DPC repair and prevention of genomic instability.

Keywords
BRCA deficiency; DNA replication; DNA-protein crosslink repair; SPRTN protease; SUMO; formaldehyde toxicity; genome stability; homologous recombination; synthetic lethality; ubiquitin.
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