Seminars

Abstract: 

Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability. We have recently discovered that R-loops, enigmatic three-stranded structures containing DNA-RNA hybrids, accumulate at sub-telomeric DNA double-strand breaks in human cells. We further identified UPF1, an RNA/DNA helicase, as a crucial factor that drives the formation of these R loops. Our data show that R loops are actively generated at DSBs to facilitate accurate DNA repair. Following this discovery, we have developed a single-molecule long-read DNA sequencing approach to characterise ultra-complex mutational events, consistent with chromoanasynthesis, occurring at these DNA double-strand breaks. Our data revealed that chromoanasynthesis is generated by microhomology-mediated break-induced replication (MM-BIR), occurring specifically in mitosis. Surprisingly, this mitotic pathway involved a novel collaboration between microhomology-mediated end-joining (MMEJ) and BIR, where MMEJ proteins initiate a Pold-dependent BIR pathway that was regulated by PIF1, POLD3 and PCNA. I will present our progress in understanding R-loops and chromoanasynthesis and further discuss the implications of our finding on the risk of developing neurodevelopmental disorders.   

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By: Paula Amiet-West
Last updated: Thursday, 29 January 2026