Transcription Dynamics in DNA Damage Response

Transcription dynamics in the context of DNA damage response encompass the interactions between RNA polymerases and lesions within the DNA template, the resulting impact on transcriptional continuity, and the recruitment of specialised repair pathways. RNA polymerase II (RNAP II) not only synthesises messenger RNA but also functions as a sensor for DNA damage. When RNAP II encounters a lesion, it may pause, stall or bypass the damage, each outcome influencing the downstream repair processes and the fidelity of gene expression.

Stalling of RNAP II at bulky or helix-distorting lesions typically serves as the signal for transcription-coupled repair (TCR), a sub-pathway of nucleotide excision repair that prioritises the transcribed strand of active genes. In contrast, small non-distorting adducts may be bypassed by the polymerase, sometimes with error, leading to transcriptional mutagenesis. The balance between pausing and bypass is modulated by elongation factors, the local chromatin environment and the nature of the lesion, thereby shaping the genome-wide distribution of mutations and influencing cell fate under genotoxic stress.

Recent advances in live-cell imaging, high-resolution mapping and quantitative modelling have begun to elucidate the kinetics of RNAP II lesion sensing, the recruitment sequence of repair factors and the probability distributions governing bypass versus repair. Such insights are critical for understanding how transcription-associated processes contribute to genomic stability, cancer aetiology and the cellular response to chemotherapeutic agents, and they offer potential avenues for therapeutic intervention by targeting specific stages of the transcriptional damage response.

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Technical terms

DNA lesion: Any chemical alteration or structural disruption in DNA bases or the backbone that can impede replication or transcription.

RNA polymerase II (RNAP II): The multisubunit enzyme responsible for transcribing protein-coding genes in eukaryotic nuclei, also acting as a damage sensor.

Transcription-coupled repair (TCR): A sub-pathway of nucleotide excision repair that is triggered by stalled RNAP II on the transcribed strand, ensuring rapid removal of lesions from active genes.

Transcriptional mutagenesis: The incorporation of incorrect ribonucleotides opposite a DNA lesion during transcription, potentially leading to aberrant or mutant mRNA and protein products.

References

1. DNA lesion bypass and the stochastic dynamics of transcription-coupled repair. Proceedings of the National Academy of Sciences of the United States of America (2024).
2. RNA polymerase pausing, stalling and bypass during transcription of damaged DNA: from molecular basis to functional consequences. Nucleic Acids Research (2022).