Beyond repair: Expanding roles of BRCA1 in RNA processing and cancer

BRCA1 is widely recognized as a guardian of the genome due to its established roles in DNA damage repair and cell cycle regulation. Nevertheless, these functions alone do not fully account for the tissue-specific defects and tumor phenotypes associated with pathogenic BRCA1 variants. Accumulating evidence indicates that BRCA1 is also essential for RNA processing. In addition to modulating the activity of RNA polymerases, shaping chromatin architecture, and interacting with key transcription factors, BRCA1 influences splicing-factor function and helps prevent and resolve R-loop accumulation, thereby regulating both transcription and genomic integrity. In response to DNA damage, BRCA1 participates in a complex containing components of the mRNA splicing machinery, thus altering the splicing pattern of several DNA damage response (DDR) genes. Moreover, BRCA1 orchestrates the transcription of molecules specific to epithelial and luminal breast cells, such as hormone receptors and growth factors, and factors involved in immune and inflammatory pathways. This review discusses and organizes the growing body of evidence demonstrating how BRCA1 integrates transcriptional control and RNA processing and, in doing so, preserves a normal epithelial phenotype.