Carnie Christopher J, Jackson Stephen P, Stingele Julian
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
Trends Cell Biol. 2025 Apr;35(4):316-329. doi: 10.1016/j.tcb.2024.11.003. Epub 2024 Nov 30.
DNA-protein crosslinks (DPCs) are highly toxic DNA lesions that are relevant to multiple human diseases. They are caused by various endogenous and environmental agents, and from the actions of enzymes such as topoisomerases. DPCs impede DNA polymerases, triggering replication-coupled DPC repair. Until recently the consequences of DPC blockade of RNA polymerases remained unclear. New methodologies for studying DPC repair have enabled the discovery of a transcription-coupled (TC) DPC repair pathway. Briefly, RNA polymerase II (RNAPII) stalling initiates TC-DPC repair, leading to sequential engagement of Cockayne syndrome (CS) proteins CSB and CSA, and to proteasomal degradation of the DPC. Deficient TC-DPC repair caused by loss of CSA or CSB function may help to explain the complex clinical presentation of CS patients.
DNA-蛋白质交联（DPCs）是与多种人类疾病相关的高毒性DNA损伤。它们由各种内源性和环境因素以及拓扑异构酶等酶的作用引起。DPCs会阻碍DNA聚合酶，触发与复制相关的DPC修复。直到最近，DPC对RNA聚合酶的阻断作用的后果仍不清楚。研究DPC修复的新方法已促成转录偶联（TC）DPC修复途径的发现。简而言之，RNA聚合酶II（RNAPII）停滞启动TC-DPC修复，导致科凯恩综合征（CS）蛋白CSB和CSA依次参与，并导致DPC的蛋白酶体降解。由CSA或CSB功能丧失引起的TC-DPC修复缺陷可能有助于解释CS患者复杂的临床表现。
