SRSF2 Regulation of Reveals Splicing as a Therapeutic Vulnerability of the p53 Pathway.

is an oncogene and critical negative regulator of tumor suppressor p53. Genotoxic stress causes alternative splicing of transcripts, which leads to alterations in p53 activity and contributes to tumorigenesis. is one of the alternatively spliced transcripts predominantly produced in response to genotoxic stress, and is comprised of terminal coding exons 3 and 12. Previously, we found that SRSF1 induces by promoting exon 11 skipping. Here we report that splicing regulator SRSF2 antagonizes the regulation of SRSF1 by facilitating the inclusion of exon 11 through binding at two conserved exonic splicing enhancers. Overexpression of SRSF2 reduced the generation of under genotoxic stress, whereas SRSF2 knockdown induced the expression of in the absence of genotoxic stress. Blocking the exon 11 SRSF2-binding sites using oligonucleotides promoted splicing and induced p53 protein expression, and apoptosis in p53 wild-type cells. The regulation of splicing by SRSF2 is also conserved in mice, as mutation of one SRSF2-binding site in exon 11, using CRISPR-Cas9, increased the expression of the homolog . IMPLICATIONS: Taken together, the data indicate that modulating splicing may be a useful tool for fine-tuning p53 activity in response to genotoxic stress.