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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.

Original publication




Journal article


Cell Rep

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BRCA deficiency, DNA replication, DNA-protein crosslink repair, SPRTN protease, SUMO, formaldehyde toxicity, genome stability, homologous recombination, synthetic lethality, ubiquitin, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, DNA Replication, DNA, Neoplasm, DNA-Binding Proteins, Female, Genomic Instability, HEK293 Cells, HeLa Cells, Homologous Recombination, Humans, Male, Proteolysis, Sumoylation, Synthetic Lethal Mutations