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

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-de...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 37; H. 10; S. 110080
Hauptverfasser: Ruggiano, Annamaria, Vaz, Bruno, Kilgas, Susan, Popović, Marta, Rodriguez-Berriguete, Gonzalo, Singh, Abhay N., Higgins, Geoff S., Kiltie, Anne E., Ramadan, Kristijan
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 07.12.2021
Cell Press
Schlagworte:
BRCA deficiency
DNA Breaks, Double-Stranded
DNA Damage
DNA Repair
DNA Replication
DNA, Neoplasm - biosynthesis
DNA, Neoplasm - genetics
DNA, Neoplasm - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
DNA-protein crosslink repair
Female
formaldehyde toxicity
genome stability
Genomic Instability
HEK293 Cells
HeLa Cells
Homologous Recombination
Humans
Male
Proteolysis
SPRTN protease
SUMO
Sumoylation
Synthetic Lethal Mutations
synthetic lethality
ubiquitin
genome stability
DNA replication
SUMO
homologous recombination
DNA-protein crosslink repair
SPRTN protease
synthetic lethality
formaldehyde toxicity
BRCA deficiency
ubiquitin
ISSN:2211-1247, 2211-1247
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Zusammenfassung: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. [Display omitted] •SUMOylation and ubiquitylation enable DPC repair during DNA replication•Resolution of ubiquitylated and SUMOylated DPCs requires the protease SPRTN•Inactivation of SUMOylation after DPC formation activates homologous recombination•DPC SUMOylation and SPRTN prevent recombination-dependent genomic instability Ruggiano et al. show that ubiquitylation and SUMOylation of DNA-protein crosslinks is linked to repair by SPRTN during DNA replication. Blocking SUMOylation causes double-strand breaks and switches the repair pathway to homologous recombination, potentially causing chromosomal rearrangements and genomic instability. Inactivation of DPC repair causes synthetic lethality in recombination-defective cells.
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Present address: The Rowett Institute, University of Aberdeen, Foresterhill Road, Aberdeen AB25 2ZD, UK
These authors contributed equally
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2021.110080