Serine Starvation Modulates mRNA Splicing Through Depletion of SR Proteins

Serine is a critical nutrient for cancer cell proliferation due to its numerous downstream functions in protein, nucleotide, and lipid biosynthesis. There are ongoing clinical efforts to utilize dietary serine starvation as a potential therapy for serine auxotrophic tumors that cannot make their own serine and are dependent on exogenous serine for growth. This emphasizes the importance of understanding how cancer cells respond to serine starvation. Here, we demonstrate that serine starvation induces dramatic changes in mRNA splicing. These effects are due, in part, to reduced translation of serine-rich proteins in serine-starved conditions, including the serine/arginine-rich splicing factor (SRSF) proteins that are known regulators of mRNA splicing. Indeed, we have found that translation of the SRSF family member SRSF6 is reduced upon serine starvation in serine auxotrophic cells and contributes to the mRNA splicing changes seen upon serine deprivation. Further, we demonstrate that reduced SRSF6 impacts the DNA damage response and cell survival in the absence of exogenous serine. Finally, we demonstrate that modulators of RNA splicing may synergize with dietary serine starvation to inhibit tumor growth.