Transcription-coupled repair

Transcription-coupled repair is a DNA repair mechanism which operates in tandem with transcription. The activity of TCR has been known for 20 years, but its mechanism of action is an area of current research. Failure of the transcription-coupled repair is the cause of Cockayne syndrome, an extreme form of accelerated aging that is fatal early in life.

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Mechanism

Genes are copied from DNA to make messenger RNA to instruct protein synthesis by RNA polymerase II. When RNA polymerase finds a lesion in the DNA, like those caused by UV light it stops and the gene is not transcribed. TCR is associated with RNA polymerase II, and the stalled RNAP is the trigger for TCR both in prokaryotes and eukaryotes.

Researchers looked at the CSB protein, which is mutated in patients with Cockayne syndrome, and found that it associated with XPG (another protein associated with the syndrome) and found that RNA polymerase II is stalled during transcription, XPG and CSB respond to the stalled transcription bubble. They then recruit transcription factor II H and other proteins and protein complexes to remodel RNA polymerase, gain access to the bubble, and repair the lesion while leaving polymerase in place.

Other repair mechanisms are possible but less accurate and efficient.

TCR also exists in bacteria, and is mediated by the TRCF (Mfd) protein. TRCF is an SF2 ATPase that uses ATP hydrolysis to translocate on dsDNA upstream of the transcription bubble and forward translocate RNA Polymerase, thus initiating dissociation of the RNA Polymerase ternary elongation complex. TRCF also recruits the Uvr(A)BC nucleotide excision repair machinery by direct physical interaction with the UvrA subunit.

References

• Sarker, A. H. et al. 2005. Recognition of RNA Polymerase II and Transcription Bubbles by XPG, CSB, and TFIIH: Insights for Transcription-Coupled Repair and Cockayne Syndrome Molecular Cell 20:187-198

• Deaconescu, A.M. et al. 2006. Structural basis for bacterial transcription-coupled DNA repair. Cell 124(3):507-520
• Deaconescu, A.M., Savery, N.J., Darst, S.A. The bacterial transcription-repair coupling factor. Curr Opin Struct Biol (2007) 1:96-102