荷兰伊拉斯谟大学医学中心Jurgen A. Marteijn课题组发现，利用CSB和CRL4CSA介导降解进行转录耦合DNA蛋白交联修复。2024年4月10日出版的《自然-细胞生物学》发表了这项成果。

研究人员发现DNA蛋白交联（DPC）会严重阻碍RNA聚合酶II介导的转录，并通过转录偶联DPC（TC-DPC）修复优先修复活性基因。转录耦合核苷酸切除修复（TC-NER）因子CSB和CSA招募到DPC停滞的RNA聚合酶II，从而启动TC-DPC修复。

CSA和CSB是TC-DPC修复不可或缺的因素，但下游TC-NER因子UVSSA和XPA却不是，这表明存在一种非经典的TC-NER机制。TC-DPC修复功能独立于SPRTN，其由泛素连接酶CRL4CSA和蛋白酶体介导。因此，基因中的DPC优先以转录耦合的方式进行修复，以保证转录不受干扰。

据悉，DPC是酶中间产物、新陈代谢或化疗药物等产生的化学物质。DPCs具有很强的细胞毒性，因为它们会阻碍DNA复制等DNA生物过程，这种作用可以通过蛋白水解酶（SPRTN）或蛋白酶体介导的DPC清除来消除。然而，，在很大程度上DPCs是否会影响转录以及转录受阻DPCs是如何修复的仍是未知。

附：英文原文

Title: Transcription-coupled DNA–protein crosslink repair by CSB and CRL4CSA-mediated degradation

Author: van Sluis, Marjolein, Yu, Qing, van der Woude, Melanie, Gonzalo-Hansen, Camila, Dealy, Shannon C., Janssens, Roel C., Somsen, Hedda B., Ramadhin, Anisha R., Dekkers, Dick H. W., Wienecke, Hannah Lena, Demmers, Joris J. P. G., Raams, Anja, Dav-Martnez, Carlota, Llerena Schiffmacher, Diana A., van Toorn, Marvin, Hckes, David, Thijssen, Karen L., Zhou, Di, Lammers, Judith G., Pines, Alex, Vermeulen, Wim, Pothof, Joris, Demmers, Jeroen A. A., van den Berg, Debbie L. C., Lans, Hannes, Marteijn, Jurgen A.

Issue&Volume: 2024-04-10

Abstract: DNA–protein crosslinks (DPCs) arise from enzymatic intermediates, metabolism or chemicals like chemotherapeutics. DPCs are highly cytotoxic as they impede DNA-based processes such as replication, which is counteracted through proteolysis-mediated DPC removal by spartan (SPRTN) or the proteasome. However, whether DPCs affect transcription and how transcription-blocking DPCs are repaired remains largely unknown. Here we show that DPCs severely impede RNA polymerase II-mediated transcription and are preferentially repaired in active genes by transcription-coupled DPC (TC-DPC) repair. TC-DPC repair is initiated by recruiting the transcription-coupled nucleotide excision repair (TC-NER) factors CSB and CSA to DPC-stalled RNA polymeraseII. CSA and CSB are indispensable for TC-DPC repair; however, the downstream TC-NER factors UVSSA and XPA are not, a result indicative of a non-canonical TC-NER mechanism. TC-DPC repair functions independently of SPRTN but is mediated by the ubiquitin ligase CRL4CSA and the proteasome. Thus, DPCs in genes are preferentially repaired in a transcription-coupled manner to facilitate unperturbed transcription.

DOI: 10.1038/s41556-024-01394-y

Source: https://www.nature.com/articles/s41556-024-01394-y