The role of isoform switching and neoantigen formation in the response to radiation

Abstract

This thesis investigates the role of isoform switching in response to ionising radiation (IR) and the modulation of this process by SRSF1, a proto-oncogenic splicing factor. Utilising deep RNA-sequencing of B-cell lines from ten healthy individuals, the study reveals extensive IR-induced isoform switching across the transcriptome, leading to potentially shorter transcripts that influence DNA damage response, apoptosis, and cell cycle arrest. Intriguingly, nearly half of the genes exhibiting isoform-level changes showed no differential expression at the gene level, highlighting the importance of isoform-specific analysis in understanding cellular responses to IR. The RNA-binding protein SRSF1 is identified as a mediator of IR-induced isoform switching. Loss of SRSF1 expression, which is a common response to IR across various cell types, enhances radiosensitivity in cell lines and in cancer patients. Moreover, the thesis explores the combined effect of SRSF1 knockdown and IR on triple-negative breast cancer cells, revealing an altered antigenic landscape with 86 putative neoantigens, and therefore offering insights into novel targeted immunotherapies. The findings propose SRSF1 as a prognostic marker for radiotherapy efficacy in the short-term, and present a foundation for future therapeutic approaches targeting SRSF1 in cancer treatment.