«Transcriptional DNA double-strand breaks and human disease»

Among genomic lesions, DNA double-strand breaks (DSBs) are infrequent but among the most harmful and they have been implicated in several human diseases. Nevertheless, our understanding of how these breaks are generated and repaired in resting cells is limited. A few years ago, we reported that transcription-blocking topoisomerase I lesions prime the production of DSBs in non-replicating cells. We then identified a mechanism of their formation, showing that they arise from two closely spaced single-strand breaks on opposing DNA strands, both produced during transcription. To investigate the clinical consequences of these transcriptional DSBs, we generated cells carrying the homozygous TDP1 H493R mutation responsible for the neurodegenerative syndrome SCAN1. This mutation leads to accumulation of transcriptional DSBs due to both increased break formation and defective repair, suggesting that persistent transcriptional DSBs in non-replicating neuronal cells contribute to neurodegeneration. More recently, we found that transcriptional DSBs can also promote the emergence of secondary resistance mutations in response to targeted anticancer treatments. Hence, our findings reveal that transcription-associated DNA breaks are more frequent and clinically relevant than previously appreciated, highlighting a critical link between transcriptional stress and disease etiology