The serine-/arginine-rich splicing factor 2 (SRSF2) plays pivotal roles in pre-mRNA processing and gene transcription. Recurrent mutations, particularly a proline-to-histidine substitution at position 95 (P95H), are common in neoplastic diseases. Here, we assess SRSF2’s diverse functions in squamous cell carcinoma. We show that SRSF2 deletion or homozygous P95H mutation both cause extensive DNA damage leading to cell-cycle arrest. Mechanistically, SRSF2 regulates efficient …