Transcription-blocking DNA lesions (TBLs) in genomic DNA are triggered by a wide variety of DNA-damaging agents. Such lesions cause stalling of elongating RNA polymerase II (RNA Pol II) enzymes and fully block transcription when unresolved. The toxic impact of DNA damage on transcription progression is commonly referred to as transcription stress. In response to RNA Pol II stalling, cells activate and employ transcription-coupled repair (TCR) machineries to repair cytotoxic TBLs and resume transcription. Increasing evidence indicates that the modification and processing of stalled RNA Pol II is an integral component of the cellular response to and the repair of TBLs. If TCR pathways fail, the prolonged stalling of RNA Pol II will impede global replication and transcription as well as block the access of other DNA repair pathways that may act upon the TBL. Consequently, such prolonged stalling will trigger profound genome instability and devastating clinical features. In this review, we will discuss the mechanisms by which various types of TBLs are repaired by distinct TCR pathways and how RNA Pol II processing is regulated during these processes. We will also discuss the clinical consequences of transcription stress and genotype-phenotype correlations of related TCR-deficiency disorders.

基因组 DNA 中的转录阻断 DNA 损伤 (TBL) 由多种 DNA 损伤剂触发。此类病变会导致延长的 RNA 聚合酶 II (RNA Pol II) 酶停滞，并在未解决时完全阻断转录。DNA 损伤对转录进程的毒性影响通常被称为转录应激。响应 RNA Pol II 停滞，细胞激活并使用转录偶联修复 (TCR) 机制来修复细胞毒性 TBL 并恢复转录。越来越多的证据表明，停滞的 RNA Pol II 的修饰和加工是细胞对 TBLs 的反应和修复的一个组成部分。如果 TCR 途径失败，RNA Pol II 的长期停滞将阻碍全局复制和转录，并阻止可能作用于 TBL 的其他 DNA 修复途径的进入。因此，这种长时间的停滞将引发严重的基因组不稳定性和破坏性的临床特征。在这篇综述中，我们将讨论不同 TCR 通路修复各种类型的 TBL 的机制，以及在这些过程中如何调节 RNA Pol II 加工。我们还将讨论转录应激的临床后果和相关 TCR 缺陷疾病的基因型-表型相关性。我们将讨论通过不同的 TCR 途径修复各种类型的 TBL 的机制以及在这些过程中如何调节 RNA Pol II 加工。我们还将讨论转录应激的临床后果和相关 TCR 缺陷疾病的基因型-表型相关性。我们将讨论通过不同的 TCR 途径修复各种类型的 TBL 的机制以及在这些过程中如何调节 RNA Pol II 加工。我们还将讨论转录应激的临床后果和相关 TCR 缺陷疾病的基因型-表型相关性。