1. Academic Validation
  2. The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability

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

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: kristijan.ramadan@oncology.ox.ac.uk.
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108702
    99.90%, SUMO-Activating Enzyme Inhibitor