Transcription-coupled nucleotide excision repair machinery (TC-NER)

Transcription-coupled nucleotide excision repair (TC-NER) is a specialized DNA repair pathway that prioritizes the removal of bulky DNA lesions from the template strands of actively transcribed genes (Marteijn et al., 2014, Nature Reviews Molecular Cell Biology). The process is initiated when RNA polymerase II stalls at a lesion, triggering the recruitment of essential proteins such as ERCC6 (CSB) and ERCC8 (CSA) to the site of damage (UniProt P28748, P54351). These proteins facilitate the assembly of the core NER machinery, including the TFIIH complex and the XPG/ERCC1-XPF nucleases, to excise the damaged segment and allow transcription to resume (PubMed: 23503575). TC-NER is critical for maintaining genomic integrity and preventing transcription-induced cell death. Mutations in TC-NER components lead to severe clinical phenotypes, most notably Cockayne syndrome, which is characterized by growth failure, neurodegeneration, and premature aging (NIH GeneReviews). In the context of cancer therapy, TC-NER serves as a double-edged sword; it contributes to resistance against platinum-based chemotherapeutics by repairing drug-induced DNA adducts, but it also presents a vulnerability that can be exploited by drugs like Irofulven, which are particularly toxic to cells with compromised repair capacity (PubChem CID 104850).

Other names

Transcription-coupled repairTCRTC-NER pathwayTranscription-coupled DNA repair

Inhibition of TC-NER prevents the removal of transcription-blocking DNA lesions, leading to persistent RNA polymerase II stalling and induction of apoptosis in cancer cells; conversely, TC-NER can be a resistance mechanism by repairing platinum-induced DNA adducts.