Transcription-Coupled DNA Damage Repair Mechanisms

Transcription-coupled DNA damage repair represents a specialised branch of nucleotide excision repair that ensures rapid removal of lesions from the transcribed strand of active genes. When RNA polymerase II (Pol II) encounters bulky adducts or UV-induced photoproducts, it stalls and triggers a highly coordinated response. Cockayne syndrome group B protein (CSB) recognises the arrested polymerase and recruits CSA and UV-stimulated scaffold protein A (UVSSA), forming a platform for the CRL4CSA ubiquitin ligase. Site-specific ubiquitylation of the RPB1 subunit of Pol II facilitates recruitment of the core transcription factor IIH (TFIIH), which unwinds DNA around the lesion and enables dual incision of the damaged strand. Subsequent gap filling and ligation restore template integrity, allowing transcription to resume. Beyond lesion excision, regulatory mechanisms including polymerase degradation, transcription shutdown and chaperone-mediated autophagy serve to fine-tune repair kinetics and maintain genome stability. Deficiencies in this pathway underlie disorders such as Cockayne syndrome and xeroderma pigmentosum and have profound implications for cancer susceptibility and ageing.

Research from Nature Portfolio

Recent studies have elucidated the molecular choreography of polymerase arrest and repair factor assembly. High-resolution cryogenic electron microscopy has revealed how ELOF1 acts as an adaptor to position UVSSA and the CRL4CSA ligase on arrested Pol II, promoting neddylation-dependent activation of RPB1 ubiquitylation and preventing premature polymerase reactivation. Complementary structural work has provided a model for human transcription–repair coupling, showing that CSB supplants elongation factor DSIF and uses its translocase activity to pull upstream DNA, while CRL4CSA bridges over the polymerase clamp to direct ubiquitylation and TFIIH recruitment. In parallel, genome-wide mapping of trabectedin-induced adducts has demonstrated that abortive transcription-coupled repair generates persistent single-strand breaks preferentially in active gene bodies and promoter regions. These insights both advance the mechanistic understanding of repair factor dynamics and offer a framework for exploiting TC-NER dependencies in precision oncology.

Transcription-Coupled DNA Damage Repair Mechanisms publication trend

The graph below shows the total number of articles in transcription-coupled dna damage repair mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Transcription-coupled nucleotide excision repair (TC-NER): A DNA repair subpathway that removes lesions from the transcribed strand by coupling repair to RNA polymerase II stalling.

RNA polymerase II (Pol II): The multi-subunit enzyme responsible for synthesising messenger RNA in eukaryotic cells.

Ubiquitylation: The covalent attachment of ubiquitin to target proteins, often marking them for degradation or regulating their activity.

Chaperone-mediated autophagy (CMA): A selective form of autophagy in which chaperone proteins deliver specific substrates to lysosomes for degradation.

Transcription factor IIH (TFIIH): A multi-protein complex that unwinds DNA around lesions and provides helicase activity during nucleotide excision repair.

References

1. Transcription-Coupled Nucleotide Excision Repair and the Transcriptional Response to UV-Induced DNA Damage. Annual Review of Biochemistry (2023).
2. Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes. Nature Communications (2024).
3. Heat shock protein DNAJA2 regulates transcription-coupled repair by triggering CSB degradation via chaperone-mediated autophagy. Cell Discovery (2023).
4. Structural basis for RNA polymerase II ubiquitylation and inactivation in transcription-coupled repair. Nature Structural & Molecular Biology (2024).
5. Elf1 promotes Rad26’s interaction with lesion-arrested Pol II for transcription-coupled repair. Proceedings of the National Academy of Sciences of the United States of America (2024).
6. The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nature Communications (2020).
7. Structural basis of human transcription–DNA repair coupling. Nature (2021).