SRSF1 coordinates transcription and alternative splicing to modulate p53 and genome-maintenance

Serine/arginine-rich splicing factor 1 (SRSF1) regulates alternative splicing and acts as a proto-oncogene, but its role in transcription remains poorly defined. We combined time-course RNA-seq with experimental validation to define SRSF1-dependent transcriptional and splicing programs. We validated 67 of 143 alternative-splicing events selected for experimental analysis. Among these, 44 were not annotated in GENCODE, including 15 containing previously unannotated exons. Thirty-five events showed concordant regulation in HEK293 and breast and prostate cancer cell lines, and 17 events in 16 genes affected p53 regulation or p53-dependent functions. SRSF1 overexpression reduced total p53, increased basal Ser15 phosphorylation, and increased apoptosis under basal and cisplatin-treated conditions but not following doxorubicin treatment. SRSF1 also increased transcription of 28 genes, 18 of which showed concordant regulation across the same cellular models. Mechanistic studies linked SRSF1-dependent transcriptional activation to P-TEFb mobilization from the 7SK snRNP, which controls P-TEFb availability for RNA polymerase II elongation. These findings identify distinct but concurrent SRSF1-regulated programs: transcriptional activation of genes associated with cellular signaling and organization and alternative splicing modulating genome-maintenance and p53-regulatory genes.