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

Transcription-coupled nucleotide excision repair (TC-NER) is a specialized DNA repair sub-pathway dedicated to the rapid removal of helix-distorting DNA lesions from the transcribed strands of active genes (Marteijn et al., 2014). This process is initiated when RNA polymerase II (RNAPII) encounters a DNA adduct, such as those formed by UV radiation or platinum-based chemotherapeutics, and becomes stalled. The stalled RNAPII serves as a scaffold for the recruitment of essential TC-NER factors, including CSB (ERCC6), CSA (ERCC8), and UVSSA, which subsequently recruit the core NER machinery to excise the damage (UniProt P28748, Q13323). TC-NER is critical for maintaining transcriptional flow and preventing apoptosis triggered by persistent transcriptional blocks. In oncology, TC-NER activity is a major determinant of resistance to DNA-damaging agents like cisplatin, as it efficiently removes cytotoxic adducts (PubMed 24662222). Conversely, certain drugs like trabectedin exploit this machinery to generate lethal double-strand breaks, making TC-NER-proficient cells more sensitive (PubMed 11560993). Deficiencies in this machinery lead to severe developmental and neurological disorders, most notably Cockayne syndrome (NIH/GARD).

Other names

Transcription-coupled repairTCRTranscription-coupled DNA repairCS-related repairTranscription-coupled nucleotide excision repair machinery at DNA adduct sites

TC-NER is triggered by RNA polymerase II stalling at DNA lesions, leading to the recruitment of CSB and CSA proteins which coordinate the excision of the damaged DNA segment by the core NER machinery (Marteijn et al., 2014). Platinum drugs create the adducts that this machinery repairs, while trabectedin exploits the machinery to create lethal breaks (PubMed 11560993).