Transcription-Coupled DNA Repair Mechanisms in Bacterial Systems

Transcription-coupled repair (TCR) represents a specialised subpathway of nucleotide excision repair that accelerates removal of lesions on the transcribed strand of active genes. In bacteria, DNA damage such as cyclobutane pyrimidine dimers or oxidative base modifications stalls RNA polymerase, triggering recruitment of a dedicated coupling factor. The prototypical coupling factor, Mfd, recognises stalled transcription elongation complexes, utilising ATP-dependent translocase activity to displace RNA polymerase and expose the lesion. Following displacement, Mfd recruits the Uvr(A)BC excinuclease complex to incise and remove the damaged oligonucleotide, after which DNA polymerase I and DNA ligase restore sequence continuity. Alternative pathways involving helicases such as UvrD and the stringent-response regulator ppGpp have been proposed to facilitate backtracking-mediated TCR, though their genome-wide contributions in Escherichia coli appear limited. TCR is not only a DNA maintenance mechanism but also influences mutagenesis rates and adaptive evolution, particularly under oxidative stress. Coordination between transcription dynamics and DNA repair ensures rapid restoration of genetic information in essential genes, thereby maintaining cellular viability and limiting deleterious mutations. Recent advances in single-molecule imaging, cryo-electron microscopy and genome-wide sequencing now elucidate molecular details of coupling factor engagement, lesion recognition and repair complex assembly, offering a comprehensive view of how bacteria preserve genome integrity in the face of frequent transcription-blocking lesions.

Research from Nature Portfolio

Advanced live-cell single-molecule imaging has revealed that the transcription–repair coupling factor associates continuously with elongating RNA polymerase even in the absence of exogenous DNA damage. Residence-time measurements indicate that coupling factor foci persist on the bacterial chromosome throughout normal growth, suggesting a constitutive housekeeping role for resolving transient transcriptional arrests. Furthermore, the presence of the excinuclease UvrA accelerates dissociation of these complexes, underscoring a coordinated hand-off mechanism between RNA polymerase rescue and lesion repair initiation during transcription elongation.

Transcription-Coupled DNA Repair Mechanisms in Bacterial Systems publication trend

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

Technical terms

Transcription-coupled repair (TCR): Subpathway of nucleotide excision repair that specifically targets lesions blocking transcription by recognising stalled RNA polymerase.

Mfd (transcription–repair coupling factor): ATP-dependent translocase that recognises stalled transcription complexes, displaces RNA polymerase and recruits NER excinuclease components.

Nucleotide excision repair (NER): Versatile DNA repair pathway that excises bulky, helix-distorting lesions and replaces excised segments via coordinated cleavage, synthesis and ligation.

RNA polymerase backtracking: Rearward movement of RNA polymerase along DNA, which can facilitate alternative lesion-recognition and repair pathways.

Endogenous oxidative stress: Reactive oxygen species generated within cells that produce base modifications and strand breaks, challenging genome integrity.

References

1. Molecular Mechanisms of Transcription-Coupled Repair. Annual Review of Biochemistry (2023).
2. The transcription-repair coupling factor Mfd associates with RNA polymerase in the absence of exogenous damage. Nature Communications (2018).
3. Structural basis for transcription complex disruption by the Mfd translocase. eLife (2021).
4. Oxidative stress drives mutagenesis through transcription-coupled repair in bacteria. Proceedings of the National Academy of Sciences of the United States of America (2023).
5. Inhibiting the Evolution of Antibiotic Resistance. Molecular Cell (2018).
6. The Mfd protein is the transcription-repair coupling factor (TRCF) in Mycobacterium smegmatis. Journal of Biological Chemistry (2023).