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

Serine/arginine-rich splicing factor 1, or SRSF1, is a proto-oncogene that influences alternative splicing and may also play a role in transcription, although its transcriptional functions have not been well understood. Researchers utilized time-course RNA-seq in conjunction with experimental confirmation to elucidate SRSF1-dependent transcriptional and splicing processes.

Out of the 143 alternative-splicing events selected for analysis, 67 were experimentally validated. Among these, 44 had not been previously annotated in the GENCODE database, including 15 involving novel exons. Thirty-five of these events demonstrated consistent regulation in both HEK293 cells and cancerous breast and prostate cell lines, while 17 events in 16 different genes impacted p53 regulation or related functions.

SRSF1 overexpression led to decreased levels of total p53, elevated phosphorylation of Ser15 in p53, and enhanced apoptosis under both normal and cisplatin treatment conditions. However, this effect was not observed with doxorubicin treatment. Furthermore, SRSF1 stimulated transcription of 28 genes, 18 of which exhibited parallel regulation across the identical cellular models.

These findings are supported by mechanistic investigations revealing that SRSF1-dependent transcriptional activation is linked to the mobilization of P-TEFb from the 7SK snRNP. This process governs P-TEFb's availability for RNA polymerase II elongation, a critical step in the transcription process. The study elucidates two concurrent SRSF1-regulated pathways: transcriptional activation of genes involved in cellular signaling and organization, and alternative splicing that modulates genes associated with genome maintenance and p53 regulatory functions.