Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while triggering excision of others is incompletely understood. Here we build structural models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in nucleotide-free and bound states. This enables simulations and graph-theoretical analyses to define partitioning of this complex into dynamic communities and delineate how its structural elements function together to remodel DNA. We identify an allosteric pathway coupling motions of the Rad26 ATPase modules to changes in RNA polymerase and DNA to unveil a structural mechanism for CSB-assisted progression past less bulky lesions. Our models allow functional interpretation of the effects of Cockayne syndrome disease mutations.

转录偶联修复对于从转录基因组中去除 DNA 损伤至关重要。该途径由 CSB 蛋白与停滞的 RNA 聚合酶 II 结合启动。损害 CSB 功能的突变会导致严重的遗传疾病。然而，CSB 驱动 RNA 聚合酶绕过某些病变同时触发其他病变切除的 ATP 依赖机制尚不完全清楚。在这里，我们建立了在无核苷酸和结合状态下与酵母 CSB 直系同源物 Rad26 结合的 RNA 聚合酶 II 的结构模型。这使得模拟和图论分析能够定义将这个复合体划分为动态社区，并描述其结构元素如何共同作用以重塑 DNA。我们确定了 Rad26 ATPase 模块的变构途径耦合运动到 RNA 聚合酶和 DNA 的变化，以揭示 CSB 辅助进展过去较小体积病变的结构机制。我们的模型允许对 Cockayne 综合征疾病突变的影响进行功能解释。