Serine Starvation Modulates mRNA Splicing through Translational Inhibition of SRSF Proteins
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. Here, 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. Further, reduced SRSF6 impacted the 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.
Authors
- Debra A. Tonetti (ORCID: https://orcid.org/0000-0003-3650-7244)
- Vipin Rawat (ORCID: https://orcid.org/0000-0003-2070-2299)
- Prarthana Prashanth (ORCID: https://orcid.org/0009-0007-9901-4494)
- Svetlana E. Semina (ORCID: https://orcid.org/0000-0002-7992-0162)
- Jonathan L. Coloff (ORCID: https://orcid.org/0000-0003-4726-3097)
- João A. Paulo (ORCID: https://orcid.org/0000-0002-4291-413X)
- Laura M. Selfors (ORCID: https://orcid.org/0000-0002-1317-7353)
- Negar Tabatabaei
- Mukhayyo Sultonova
- Debolanle O. Dahunsi (ORCID: https://orcid.org/0000-0002-5230-022X)
- Philippa A. Burns
- Mete Emir Özgürses (ORCID: https://orcid.org/0000-0002-8472-3948)
- Hao Fan (ORCID: https://orcid.org/0000-0002-9281-8760)
- Soroush Tahmasebi (ORCID: https://orcid.org/0000-0002-2807-5480)
- Francine E. Garrett-Bakelman (ORCID: https://orcid.org/0000-0002-4771-628X)
- J. Patrick Murphy (ORCID: https://orcid.org/0000-0003-4074-359X)
- Godwin K. Sarpey
- Huiping Zhao (ORCID: https://orcid.org/0009-0004-4572-734X)
- Aanshi Vashi (ORCID: https://orcid.org/0009-0005-7998-6902)
Institutions
- Harvard University (US)
- University of Prince Edward Island (CA)
- Harvard University Press (US)
- University of Massachusetts Boston (US)
- University of Illinois Chicago (US)
- University of Chicago (US)
- Dana-Farber/Harvard Cancer Center (US)
- University of Virginia (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2026-07-22
- DOI
- https://doi.org/10.1158/0008-5472.can-25-4971
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 0.00