Medical Research Council (MRC) Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
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.
Cell Rep. 2021 Dec 7;37(10):110080. doi: 10.1016/j.celrep.2021.110080.
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.
DNA-蛋白质交联（DPCs）是一种特定类型的 DNA 损伤，其中蛋白质与 DNA 发生共价连接。未修复的 DPC 会导致基因组不稳定、癌症、神经退行性变和加速衰老。最近发现 DPC 蛋白水解是 DPC 修复的一种特殊途径。DNA 依赖性蛋白酶 SPRTN 和 26S 蛋白酶体成为两个独立的蛋白水解系统。DPC 也可以通过同源重组（HR）进行修复，这是一种典型的 DNA 修复途径。在研究细胞对 DPC 形成的反应时，我们发现泛素化和 SUMO 化是 DNA 复制偶联 DPC 修复中的两个主要信号事件。DPC 的泛素化将 SPRTN 招募到修复部位，促进 DPC 的去除。DPC 的 SUMO 化可防止 DNA 双链断裂的形成、HR 的激活以及潜在的有害基因组重排。通过这种方式，SUMO 化将 DPC 修复引导到 SPRTN 蛋白水解，这是 DPC 修复和预防基因组不稳定的更安全途径选择。
