SRSF1 regulates response to ionizing radiation through isoform switching

Alternative splicing results in different transcript isoforms, with potentially different functions, from the same gene. Recent studies suggest that isoform switching, differential usage of gene isoforms, can impact the response to DNA damage. Here, we investigated the impact of isoform switching on the response to ionizing radiation (IR) by high-throughput sequencing. Using B-cells from 10 individuals, we identified ~1,900 IR-responsive transcript isoforms, where over a third involved exon skipping. To understand how isoform switching is mediated, we found 35 RNA binding proteins that are IR-responsive. Among them, we identified Serine/Arginine-Rich Splicing Factor 1 (SRSF1) as a mediator of most of the IR-induced isoform switching. Upon irradiation, the expression of SRSF1 decreases, leading to the expression of transcript isoforms that promote cell death. From a clinical perspective, we found that radiotherapy-treated lower-grade glioma and breast cancer patients that express low levels of SRSF1 had significantly higher survival. Together, our results identify the downregulation of SRSF1, and the resulting changes in isoform expression of its targets, as a cellular response to irradiation and highlight the clinical potential of SRSF1 as a prognostic marker for radiotherapy efficacy.