Transcription Coupled NerEdit

Transcription-coupled nucleotide excision repair (TC-NER) is a specialized arm of the broader DNA repair network that preserves the integrity of actively transcribed genes. It complements global genome nucleotide excision repair (GG-NER) by prioritizing lesions that stall transcription on the transcribed strand, thereby helping to maintain proper gene expression and cellular health when DNA damage occurs. The pathway is a key example of how cells couple DNA repair to transcription, ensuring that essential information stored in genes remains accessible and readable even in the face of environmental insults or metabolic stress.

TC-NER recognizes and rapidly removes certain helix-distorting DNA lesions—most notably those induced by ultraviolet light such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts—that block RNA polymerase II during transcription. While both TC-NER and GG-NER use the core repair machinery, TC-NER relies on a distinct set of damage-sensing and chromatin-remodeling factors to initiate repair preferentially at sites where transcription has been halted. In the broader context of nucleotide excision repair, TC-NER serves to protect the integrity of the transcriptome and to minimize the downtime of gene expression programs in cells.

Overview

TC-NER is activated when RNA polymerase II stalls at a lesion on the transcribed strand, triggering a cascade that prioritizes transcription-blocking damage.
The pathway shares the central incision enzymes with GG-NER, but it employs a specialized set of factors to recognize stalled transcription complexes and to coordinate rapid repair within actively transcribed regions.
After lesion removal, transcription can be resumed, aided by chromatin remodeling and coordinated re-entry of the transcription machinery.

Mechanism

Step 1: Stalled transcription recognition
- RNA polymerase II arrest at a DNA lesion acts as the initial signal. The transcription-blocking event leads to recruitment of TC-NER–specific factors such as CSB and CSA, which help interpret the stalled complex and recruit downstream repair proteins.
Step 2: Assembly of the TC-NER repair complex
- The CSB and CSA proteins coordinate with other factors (including UVSSA) to establish a repair-competent complex at the site. This assembly helps bridge the stalled polymerase to the core repair machinery.
Step 3: DNA unwinding and lesion verification
- The TFIIH complex, which includes helicases such as XPB and XPD, is recruited to unwind the damaged DNA. This unwinding is followed by verification of the lesion and stabilization by the single-stranded DNA binding protein complex (RPA), with involvement from the damage verification protein XPA.
Step 4: Incision and gap-filling
- Dual incisions are made by the endonucleases XPG (5’ side) and XPF-ERCC1 (3’ side), excising the damaged DNA fragment. DNA polymerases, typically from the replicative or repair-associated families, fill the gap, and DNA ligase seals the nick.
Step 5: Transcription restart
- Following repair, transcription is reinitiated. PCNA and other replication/repair factors help reassemble the transcription machinery, and chromatin remodeling facilitates access to the repaired template.
Step 6: Regulators and chromatin context
- Chromatin remodeling proteins and histone modifiers can influence repair efficiency, reflecting the importance of chromatin state in transcription-coupled repair pathways.

Core components and interactions

Damage recognition and transcription coupling: CSB (ERCC6) and CSA (ERCC8) are central to recognizing a stalled RNA polymerase II and coordinating repair factor recruitment. UVSSA also participates in stabilizing the recognition complex in many contexts.
Core NER machinery: The transcription factor–repair coupling process uses the shared NER core, notably the TFIIH complex (with the helicases XPB and XPD), along with damage verification (XPA), and the incision enzymes XPG and XPF-ERCC1.
Transcription and chromatin interfaces: The pathway is integrated with RNA polymerase II–associated processes and with chromatin remodelers that modulate accessibility near lesions.
Related disease biology: Defects in TC-NER factors underlie human disorders such as Cockayne syndrome, where patients exhibit growth and developmental abnormalities and photosensitivity, highlighting the biological importance of rapid transcription-coupled repair.

Regulation and interpathway relationships

Relationship to GG-NER: TC-NER and GG-NER share core components but diverge in their initial damage recognition steps. While GG-NER surveys the genome globally, TC-NER gates repair through transcription-coupled signals, ensuring priority repair of transcribed regions.
Coordination with transcription restart: The successful resumption of transcription after repair depends on the timely clearance of the repair intermediates and proper reassembly of the transcriptional apparatus, including regulatory signaling that restarts elongation by RNA polymerase II.
Influence of chromatin state: Nucleosome positioning, histone modifications, and chromatin remodelers influence the accessibility of damaged templates and the efficiency of repair, particularly in compact or transcriptionally active regions.

Clinical relevance and model systems

Cockayne syndrome and related disorders: Mutations in TC-NER factors such as CSB or CSA lead to Cockayne syndrome in humans, characterized by growth failure, neurodevelopmental deficits, and photosensitivity. The study of these conditions helps illuminate which components are essential for transcription-coupled repair in vivo.
Experimental models: Yeast, human cell lines, and animal models have contributed to understanding the stepwise recruitment of TC-NER factors, the balance with GG-NER, and the consequences of repair defects on transcription and genome stability.
Therapeutic implications: Insights into TC-NER pathways inform strategies for protecting cells from UV damage, improving resistance to environmental genotoxins, and understanding the molecular basis of diseases linked to repair defects.

Controversies and debates

Exact trigger signals: While stalled RNA polymerase II is a central cue for TC-NER, debates continue about whether additional signals or lesion-type specificity influence the recruitment of CSB, CSA, and UVSSA, and how these signals integrate with chromatin state.
Distinct versus overlapping roles of TC-NER factors: Some studies emphasize a clear separation between TC-NER and GG-NER factors in transcription-coupled contexts, while others argue for more fluid sharing of components depending on cell type, lesion, and chromatin context.
Role of transcription restart mechanisms: There is ongoing discussion about how quickly and by which intermediate steps transcription resumes after repair, and how repair-coupled chromatin remodeling tunes the return to productive transcription.
Pathophysiology of related disorders: The relationship between TC-NER defects and clinical phenotypes (e.g., why Cockayne syndrome features are distinct from classical xeroderma pigmentosum) remains under study, with researchers examining tissue-specific sensitivities and the potential contributions of repair-independent functions of TC-NER factors.