英国剑桥大学Julian Stingele小组发现DNA-蛋白交联的转录偶联修复依赖于CSA和CSB。该项研究成果发表在2024年4月10日出版的《自然—细胞生物学》杂志上。

据了解，共价DNA-蛋白交联(DPCs)是一种毒性DNA损伤，可阻断DNA复制，需要通过多种途径进行修复。转录阻断是否对DNA-蛋白交联的毒性有贡献，以及当RNA聚合酶在DNA-蛋白交联停止时细胞如何反应尚不清楚。

研究组发现共价DNA-蛋白交联(DPCs)的形成抑制转录并诱导RNA聚合酶II的泛素化和降解。利用基因筛选和DNA-蛋白加合物全基因组定位方法——DPC测序，研究小组发现柯凯因综合征(Cockayne syndrome, CS)蛋白CSB和CSA，通过促进活性转录基因中的DNA-蛋白交联修复来抵抗DNA-蛋白交联诱导剂。因此，CSB或CSA缺陷细胞在诱导DNA-蛋白交联后不能有效地重新启动转录。

相反，在紫外光诱导的DNA损伤中，作用于CSB和CSA下游的核苷酸切除修复因子不是必须的。他们的研究描述了一种转录偶联的DNA-蛋白交联修复途径，并表明该途径中的缺陷可能有助于柯凯因综合征独特的神经学特征。

附：英文原文

Title: Transcription-coupled repair of DNA–protein cross-links depends on CSA and CSB

Author: Carnie, Christopher J., Acampora, Aleida C., Bader, Aldo S., Erdenebat, Chimeg, Zhao, Shubo, Bitensky, Elnatan, van den Heuvel, Diana, Parnas, Avital, Gupta, Vipul, DAlessandro, Giuseppina, Sczaniecka-Clift, Matylda, Weickert, Pedro, Aygenli, Fatih, Gtz, Maximilian J., Cordes, Jacqueline, Esain-Garcia, Isabel, Melidis, Larry, Wondergem, Annelotte P., Lam, Simon, Robles, Maria S., Balasubramanian, Shankar, Adar, Sheera, Luijsterburg, Martijn S., Jackson, Stephen P., Stingele, Julian

Issue&Volume: 2024-04-10

Abstract: Covalent DNA–protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA–protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.

DOI: 10.1038/s41556-024-01391-1

Source: https://www.nature.com/articles/s41556-024-01391-1