Transcription coupled repair

Transcription-Coupled Repair
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Transcription-Coupled Repair (TCR) is a sub-pathway of the nucleotide excision repair (NER) mechanism that specifically targets and repairs DNA lesions on the transcribed strand of active genes. This process is crucial for maintaining the integrity of the genome and ensuring the proper functioning of gene expression.

Overview

Transcription-Coupled Repair is a specialized DNA repair mechanism that prioritizes the repair of DNA damage in actively transcribed genes. This is in contrast to the global genome repair (GGR) sub-pathway of NER, which repairs lesions throughout the entire genome. TCR is particularly important for the rapid removal of transcription-blocking lesions, such as those caused by ultraviolet radiation or oxidative stress.

Mechanism

The TCR process is initiated when the RNA polymerase encounters a DNA lesion on the transcribed strand during transcription. This stalling of RNA polymerase serves as a signal for the recruitment of repair proteins. The key steps in TCR include:

Recognition of DNA Damage

When RNA polymerase stalls at a lesion, it triggers the recruitment of several factors, including the Cockayne syndrome proteins CSA and CSB. These proteins play a critical role in recognizing the stalled transcription complex and initiating the repair process.

Recruitment of Repair Factors

Once the damage is recognized, the transcription machinery is displaced, and repair factors are recruited to the site. The TFIIH complex, which contains helicase activity, unwinds the DNA around the lesion. This allows for the excision of the damaged DNA segment.

Excision and Repair

The damaged DNA strand is excised by endonucleases, creating a gap. This gap is then filled in by DNA polymerase, using the undamaged strand as a template. Finally, DNA ligase seals the newly synthesized DNA into the existing strand, completing the repair process.

Biological Significance

TCR is essential for preventing mutations in actively transcribed genes, which could lead to genetic disorders or cancer. The efficiency of TCR ensures that cells can quickly resume transcription after DNA damage, maintaining cellular function and viability.

Clinical Implications

Defects in TCR are associated with several human disorders, most notably Cockayne syndrome and trichothiodystrophy. These conditions are characterized by increased sensitivity to UV light, neurological abnormalities, and premature aging. Understanding TCR mechanisms can provide insights into the development of therapeutic strategies for these disorders.

Research Directions

Current research in TCR focuses on elucidating the detailed molecular interactions between repair proteins and the transcription machinery. Advances in structural biology and genomics are providing new insights into the regulation of TCR and its integration with other cellular processes.

See Also

• Nucleotide excision repair
• DNA repair
• RNA polymerase
• Cockayne syndrome

External Links

• [Link to relevant research articles]
• [Link to educational resources]