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

Transcription-coupled nucleotide excision repair (TC-NER) is a specialized subpathway of nucleotide excision repair (NER) that specifically repairs DNA damage on actively transcribed strands. Unlike global genomic NER (GG-NER) which uses surveillance proteins like XPC to recognize damage, TC-NER utilizes elongating RNA polymerase II (Pol II) to scan the transcribed strand and identify transcription-stalling damage[1]. The TC-NER process begins when RNA polymerase II stalls at a DNA lesion. This triggers the recruitment of specific TC-NER factors, including CSB (or its counterparts Rad26 in yeast and Mfd in bacteria), which helps displace the transcription elongation factor Spt4-Spt5 in regions downstream of the transcription start site[1]. After damage recognition, both TC-NER and GG-NER pathways converge by recruiting transcription factor IIH (TFIIH), a ten-subunit complex containing the DNA helicases XPD and XPB[1][2]. TFIIH, along with XPA and replication protein A (RPA), unwinds the DNA strands around the damage site and verifies the presence of the lesion[1]. This creates a preincision DNA bubble that is recognized by repair endonucleases ERCC1-XPF and XPG, which make incisions on the 5' and 3' sides of the damage, respectively[1][2]. This dual incision results in the removal of a single-stranded DNA fragment of approximately 25-30 nucleotides containing the lesion[1][2]. Following excision, replication factor C (RFC) loads the Proliferating Cell Nuclear Antigen (PCNA) onto the DNA strand, allowing DNA polymerases (δ, ε and/or κ) to fill the gap using the undamaged strand as a template[2]. Finally, DNA ligase I or the ligase III-XRCC1 complex seals the nicks to complete the repair process[1][2]. Recent genomic approaches have revealed that TC-NER may have broader functions than previously thought, including the repair of non-bulky base damage when base excision repair (BER) is deficient[1]. Defects in TC-NER components can lead to severe human disorders, including xeroderma pigmentosum, which increases skin cancer risk by 1000-fold in homozygous patients[2]. Additionally, polymorphisms in TC-NER genes have been associated with cancer prognosis, with the XPD polymorphism 2251A>C significantly correlated with early relapse in colorectal cancer patients after chemotherapy[2].

Other names

Transcription-coupled repair (TCR)TC-NER subpathwayTranscription-coupled DNA repair complex