LSm4 biomolecular condensates drive XRN2-mediated RNA decay at DNA double-strand breaks to facilitate repair

Authors

Darawshe, M. M., Bishara, L. A., Abu-Zhayia, E. R., Barisaac, A. S., Machour, F. E., Elmor, C., Ayoub, N.

Abstract

Maintenance of genome integrity requires accurate repair of DNA double-strand breaks (DSBs), particularly within transcriptionally active regions. Persistent R-loops at DSBs can impede homologous recombination (HR) repair. While factors that resolve R-loops at DSB sites are known, the mechanisms ensuring timely degradation of nascent RNA to prevent pathological R-loop accumulation remain elusive. Here, we identified a critical role for the RNA-binding protein LSm4 in orchestrating localized RNA decay at DSBs to facilitate repair. We demonstrated that among LSm1-8 subunits, only LSm4 undergoes liquid-liquid phase separation (LLPS) and forms biomolecular condensates (BCs) specifically at DSBs in transcriptionally active chromatin. These damage-induced LSm4 BCs function as hubs that promote nuclear RNA decapping and recruit the 5'[->]3' exonuclease XRN2 to degrade nascent transcripts proximal to DSBs. Accordingly, LSm4-XRN2 axis suppresses R-loop hyperaccumulation, thereby enabling efficient RAD51 filament assembly and intact HR repair. Consequently, loss of LSm4 increases translocations and leads to genomic instability. Collectively, our findings define a new regulatory layer in which LSm4 BCs spatially license RNA degradation, preventing R-loop accumulation at DSB microenvironment to facilitate error-free repair.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Aug 2026.

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