Abstract Serine is a critical nutrient for cancer cell proliferation due to its numerous downstream biosynthetic functions. Given the ongoing clinical efforts to utilize dietary serine starvation as a potential therapy for serine auxotrophic tumors, it is important to understand how cancer cells respond to serine starvation. In this study, we demonstrated that serine starvation induces dramatic changes in mRNA splicing. These effects are due, in part, to reduced translation of serine-rich proteins, including the serine/arginine-rich splicing factor (SRSF) proteins that are known regulators of mRNA splicing. Indeed, translation of SRSF6 was reduced upon serine starvation in serine auxotrophic cancer cells and contributes to the RNA splicing changes seen upon serine deprivation. Furthermore, reduced SRSF6 affected DNA damage response and cell survival in the absence of exogenous serine, and modulators of RNA splicing combined with dietary serine starvation to inhibit tumor growth. Collectively, this work describes a fundamental role for serine in supporting mRNA splicing, which may have implications in the clinical efforts to bring dietary serine starvation to the clinic. Significance: Serine starvation induces changes in mRNA splicing by inhibiting translation of serine-rich proteins like SRSF6, which impacts the DNA damage response and could affect how cancer cells respond to chemotherapy.
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