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Updated: Oct 10, 2025
Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications
Published on: April 21, 2023
The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability
Annamaria Ruggiano1, Bruno Vaz1, Susan Kilgas1
1Medical Research Council (MRC) Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, 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.
Insights
DNA-protein crosslinks (DPCs) are repaired by ubiquitylation and SUMOylation. SUMOylation directs DPC repair to SPRTN proteolysis, preventing genomic instability and DNA double-strand breaks.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- DNA-protein crosslinks (DPCs) are DNA lesions where proteins covalently bind to DNA.
- Unrepaired DPCs cause genomic instability, cancer, neurodegeneration, and aging.
- DPC repair pathways include DPC proteolysis (via SPRTN protease and 26S proteasome) and homologous recombination (HR).
Purpose of the Study:
- To investigate the cellular signaling events involved in DNA replication-coupled DPC repair.
- To elucidate the roles of ubiquitylation and SUMOylation in DPC repair pathways.
Main Methods:
- Studied cellular responses to DPC formation.
- Investigated the roles of ubiquitylation and SUMOylation in DPC repair.
- Analyzed the recruitment of SPRTN and activation of HR.
Main Results:
- Identified ubiquitylation and SUMOylation as key signaling events in DPC repair.
- DPC ubiquitylation recruits the SPRTN protease for DPC removal.
- DPC SUMOylation prevents DNA double-strand breaks and HR activation, favoring SPRTN proteolysis.
Conclusions:
- Ubiquitylation and SUMOylation are critical regulators of DPC repair.
- SUMOylation promotes a safer repair pathway (SPRTN proteolysis) over HR, preventing genomic instability.
- This study reveals a sophisticated mechanism for managing DPC lesions during DNA replication.
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