Mechanisms of transcription-coupled repair and DNA damage surveillance in health and disease

RNA polymerase II (Pol II)-mediated gene transcription is frequently disrupted by DNA damage from various sources. Transcription-blocking DNA lesions hinder the progression of elongating Pol II, leading to transcription stress that, if unresolved, causes cellular dysfunction, neurodegeneration and ageing. In this Review, we discuss how different types of lesion are recognized by obstructing Pol II and removed by the intricate transcription-coupled nucleotide excision repair (TC-NER) pathway, emphasizing recent structural findings that reveal key aspects of the TC-NER mechanism. We also discuss the mechanisms proposed for processing lesion-stalled Pol II, which is crucial to facilitate TC-NER, and focus on how Pol II ubiquitylation orchestrates repair-complex assembly and Pol II degradation. In addition, we discuss the alternative mechanism of transcription-coupled DNA–protein crosslink repair, which was recently identified to be important for resolving DNA–protein crosslinks in active genes. Finally, we describe how these insights elucidate the different pathological causes of hereditary TC-NER deficiencies, namely of the mild cutaneous ultraviolet-sensitive syndrome and the severe progeroid Cockayne syndrome.