Abstract
SummaryDNA-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.
Highlights
DNA-protein crosslinks (DPCs) are ubiquitous and heterogeneous DNA lesions that arise from covalent binding of a protein to DNA following exposure to a chemical or physical crosslinking agent, e.g., formaldehyde (FA) or UV light (Ide et al, 2018; Ku€hbacher and Duxin, 2020; Vaz et al, 2017)
We propose that SUMOylation channels DPC repair pathway choice toward SPRTN-dependent proteolysis to prevent recombinogenic events that could lead to genomic instability
DPCs are modified by small ubiquitin-like modifier (SUMO) and ubiquitin To gain insights into the ubiquitin and SUMO signals associated with DPC repair in proliferative mammalian cells, we analyzed the dynamics of both post-translational modifications (PTMs) on DPCs following exposure to the general DPCinducing agent FA (Figures 1A and S1A)
Summary
DNA-protein crosslinks (DPCs) are ubiquitous and heterogeneous DNA lesions that arise from covalent binding of a protein to DNA following exposure to a chemical or physical crosslinking agent, e.g., formaldehyde (FA) or UV light (Ide et al, 2018; Ku€hbacher and Duxin, 2020; Vaz et al, 2017). To cope with DPC-induced toxicity, cells employ two major repair pathways: (1) a proteolytic-dependent mechanism, where the proteinaceous component of the DPC is cleaved by specific proteases; and (2) a nucleolytic-dependent mechanism, where the nucleases involved in homologous recombination (HR) or nucleotide excision repair cleave off the DNA bearing a crosslinked protein (Aparicio et al, 2016; Hoa et al, 2016; Nakano et al, 2007, 2009) The former mechanism involves DNA-dependent metalloproteases, SPRTN in metazoans and Wss in yeast (Lopez-Mosqueda et al, 2016; Maskey et al, 2017; Morocz et al, 2017; Stingele et al, 2014, 2016; Vaz et al, 2016), or the proteasome (Larsen et al, 2019; Sparks et al, 2019; Sun et al, 2020). Among them, SPRTN is the only essential gene in cells, indicating the crucial role of the protease SPRTN in DPC repair, embryogenesis, and cell survival
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