Mammalian Transcription-Coupled Excision Repair

Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients’ death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.Damaged DNA causes genome instability and reduces the fidelity of the replication process, resulting in increased mutagenesis, which are both at the basis of oncogenic transformation. In addition, lesions may block transcription, which causes disturbed cellular homeostasis and may trigger cellular senescence or apoptosis, resulting in damage-induced aging.Despite the different DNA repair processes that remove many types of DNA lesions, replication and transcription machineries frequently encounter unrepaired lesions that disturb replication fork progression and transcription elongation or may even cause stalling. The structural complexity caused by lesion-stalled replication forks and transcription elongation complexes demands alternative strategies to deal with these genomic road blocks. Additional key repair processes exist to prevent replication fork collapse and promote fork restart (e.g., translesion synthesis and homologous recombination) or to resolve stalled transcription (transcription-coupled nucleotide excision repair; TC-NER).