Michael Nicholson

Quantifying the stochastic dynamics of transcription-coupled DNA repair

DNA base damage is a major source of cancer-causing mutations and disruption to gene expression. Transcription-coupled repair (TCR) minimises the risk of damage within genes, but experimental measurement of this DNA repair process is challenging. Here, we combined a well powered murine model of cancer development with a stochastic model of damage and repair to quantify the mechanisms of TCR on DNA alkylation adducts. We show that RNA-polymerases frequently bypass lesions without triggering repair, indicating that small alkylation adducts are unlikely to be an efficient barrier to gene expression but are likely to be a source of mutant RNA. The efficiency of TCR gradually decays through gene bodies leading to a rejection of the standard conceptual model that transcription immediately resumes after repair. Our results have implications for the accurate inference of driver mutations in cancer and the effects of DNA damage on expression, especially for genes with a large genomic span.