RNA-related functions of BRCA2 in transcription, replication, and genome stability

BRCA2 is a central tumor suppressor protein best known for its roles in homologous recombination and replication fork stability. Increasing evidence, however, positions BRCA2 at the interface of transcription and replication, where it preserves genome stability under transcription-associated stress. BRCA2 regulates R-loop homeostasis, transcription-replication conflict resolution, and RNA polymerase II dynamics. Its loss leads to R-loop accumulation, transcriptional pausing, and elevated transcription-replication head-on collisions, particularly in highly transcribed regions. BRCA2 also promotes the processing of RNA-associated DNA lesions, preventing toxic intermediates during S phase. Through interactions with factors such as PAF1, PCAF, and DDX5, BRCA2 coordinates transcription, chromatin regulation, and DNA-RNA hybrid resolution, linking these processes to inflammatory and stress-responsive transcriptional programs, including NF-κB signaling. In this review, we focus on the emerging roles of BRCA2 in transcription-related pathways, including R-loop homeostasis, resolution of transcription-replication conflicts, RNA polymerase II dynamics, and broader transcriptional regulation.