Cancer-specific chemo-neoepitopes arising from abnormal splicing induced by the chemotherapeutic agent 5-fluorouracil (5-FU).

ABSTRACT: Chemotherapy exerts anti-tumor effects in part because cancer cells respond differently from normal cells to DNA damage. However, chemotherapeutic agents can damage not only DNA but also RNA components of the spliceosome. Consequently, chemotherapy may induce transient inhibition of pre-mRNA splicing, manifested as widespread intron retention. The pattern of DNA damage-induced intron retention is recurrent and reproducible in cells exposed to the same chemotherapeutic agent. Translation of transcripts containing retained introns may generate shared, non-mutated neoantigens (neo-Ags) encoded by intronic sequences. Responses to chemotherapy-induced DNA damage may also differ between normal and cancer cells, particularly when p53 function is disrupted. For example, transcription of a subset of genes involved in cell proliferation may be repressed in normal cells but maintained in cancer cells harboring p53 mutations. These differences may promote the generation of cancer-specific, non-mutated neo-antigens encoded by retained introns. Some of these novel intron-derived peptides may contain highly immunogenic neoepitopes recognizable by cytotoxic T lymphocytes (CTLs). To investigate the feasibility of identifying cancer-specific aberrant splicing events, including intron retention, we performed RNA sequencing (RNA-seq) analysis of two isogenic variants of the AT-3 mouse breast cancer cell line: one retaining wild-type p53 and the other with p53 inactivated by CRISPR–Cas9. Both variants were treated with 50 µM 5-fluorouracil (5-FU) for 24 hours or left untreated. The cytoplasmic RNA was sequenced using Illumina platform

ORGANISM(S): Mus musculus

PROVIDER: GSE353106 | GEO | 2026/11/04

REPOSITORIES: GEO