LSm4 protein forms RNA degradation hubs at DNA breaks to facilitate repair
Accurate repair of DNA double-strand breaks (DSBs) is essential for genomic stability, especially in transcriptionally active regions. Persistent transcription at DSBs leads to the formation of RNA:DNA hybrids (R-loops), which obstruct homologous recombination (HR). While R-loop resolution is understood, the mechanisms that remove pre-existing RNA transcripts in the vicinity of DSBs to limit R-loop formation remain poorly understood. In my PhD, I describe a mechanism by which cells locally degrade RNA at DSBs to enable repair. I show that the RNA-binding protein LSm4 is rapidly recruited to DSBs in active chromatin, where it undergoes liquid-liquid phase separation (LLPS) to form biomolecular condensates. These condensates function as processing hubs that promote RNA decapping and recruit the 5′→3′ exonuclease XRN2 to degrade nascent transcripts near the break. This LSm4–XRN2 axis suppresses pathological R-loop accumulation, facilitating RAD51 recruitment and accurate HR. Loss of LSm4 leads to genomic instability and increased translocations. These findings establish phase-separated condensates as spatial organizers of RNA clearance at DNA lesions, revealing a new paradigm for coordinating local RNA turnover with faithful DNA repair.
