Myelodysplastic Syndrome-Associated SRSF2 Mutations Cause Splicing Changes by Altering Binding Motif Sequences

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Serine/arginine-rich splicing factor 2 (SRSF2) regulates mRNA splicing.
• SRSF2 gene mutations are frequently found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Purpose of the Study:

• To characterize MDS-associated SRSF2 mutants (P95H, P95L, P95R).
• To investigate how SRSF2 mutations affect SRSF2-mediated splicing in MDS.

Main Methods:

• Nuclear localization of SRSF2 mutants was assessed in HeLa cells.
• In vitro splicing assays were performed.
• RNA sequencing was used to analyze splicing patterns in K562 cell lines expressing wild-type or mutant SRSF2.

Main Results:

• MDS-associated SRSF2 mutants and wild-type proteins localize to the nucleus and participate in splicing.
• Both wild-type and mutant SRSF2 affected splicing of approximately 3,000 genes.
• Exonic motif analyses revealed distinct binding sequences for wild-type and mutant SRSF2, indicating altered RNA binding properties.

Conclusions:

• Mutations in SRSF2 in MDS alter its binding to exonic motifs.
• These altered binding properties lead to aberrant mRNA splicing, contributing to MDS pathogenesis.