Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia.
DNA Repair (Amst). 2018 Nov;71:198-204. doi: 10.1016/j.dnarep.2018.08.025. Epub 2018 Aug 23.
DNA-protein crosslinks (DPCs) are a specific type of DNA lesion consisting of a protein covalently and irreversibly bound to DNA, which arise after exposure to physical and chemical crosslinking agents. DPCs can be bulky and thereby pose a barrier to DNA replication and transcription. The persistence of DPCs during S phase causes DNA replication stress and genome instability. The toxicity of DPCs is exploited in cancer therapy: many common chemotherapeutics kill cancer cells by inducing DPC formation. Recent work from several laboratories discovered a specialized repair pathway for DPCs, namely DPC proteolysis (DPCP) repair. DPCP repair is carried out by replication-coupled DNA-dependent metalloproteases: Wss1 in yeast and SPRTN in metazoans. Mutations in SPRTN cause premature ageing and liver cancer in humans and mice; thus, defective DPC repair has great clinical ramifications. In the present review, we will revise the current knowledge on the mechanisms of DPCP repair and on the regulation of DPC protease activity, while highlighting the most significant unresolved questions in the field. Finally, we will discuss the impact of faulty DPC repair on disease and cancer therapy.
DNA-蛋白质交联物（DPCs）是一种特殊类型的 DNA 损伤，由蛋白质与 DNA 发生不可逆的共价结合而形成，这些损伤通常在暴露于物理和化学交联剂后产生。DPCs 体积较大，因此会对 DNA 复制和转录造成障碍。在 S 期，DPCs 的持续存在会导致 DNA 复制应激和基因组不稳定性。DPCs 的毒性被用于癌症治疗：许多常见的化疗药物通过诱导 DPC 的形成来杀死癌细胞。来自几个实验室的最近研究发现了 DPC 的一种专门修复途径，即 DPC 蛋白水解（DPCP）修复。DPCP 修复是由复制偶联的 DNA 依赖性金属蛋白酶完成的：酵母中的 Wss1 和后生动物中的 SPRTN。SPRTN 基因突变会导致人类和小鼠过早衰老和肝癌；因此，DPC 修复缺陷具有重要的临床意义。在本综述中，我们将回顾 DPCP 修复机制和 DPC 蛋白酶活性的调控方面的最新知识，同时强调该领域最显著的未解决问题。最后，我们将讨论错误的 DPC 修复对疾病和癌症治疗的影响。
