SRSF2, or Serine and Arginine Rich Splicing Factor 2, is a protein found in human cells and broadly expressed across various cell types. It belongs to the serine/arginine (SR)-rich family of pre-messenger RNA (pre-mRNA) splicing factors and is considered a normal component of the nuclear speckle structure. SRSF2 plays a fundamental role in genetic processes, essential for proper cell function and overall health.
SRSF2’s Core Function: RNA Splicing
SRSF2’s primary function is RNA splicing, a fundamental step in gene expression. RNA splicing removes non-coding regions, called introns, from a newly made RNA molecule. The remaining coding regions, called exons, are then joined together. This transforms pre-mRNA into mature messenger RNA (mRNA), which carries instructions for building specific proteins.
SRSF2 contributes to this process by recognizing and binding to specific RNA sequences on the pre-mRNA, primarily through its RNA recognition motif (RRM) domain. It also interacts with other splicing factors via its arginine/serine-rich (RS) domain, facilitating the assembly of the spliceosome, the molecular machine responsible for splicing. This coordinated action ensures that exons are accurately assembled, which is vital for producing functional proteins.
When SRSF2 Goes Awry: Implications for Health
When SRSF2 malfunctions due to mutations or dysregulation, it can impact human health. Mutations in SRSF2 are frequently observed in patients with myeloid neoplasms, a type of blood cancer. These include Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML).
SRSF2 mutations are among the most common splicing mutations linked to AML, and their presence in a healthy individual carries a high risk of progression to AML. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations are found in a high frequency, ranging from 28% to 47% of cases. These mutations are often associated with specific clinical features, such as multilineage dysplasia and excess blasts in MDS, and can influence how the disease progresses.
How SRSF2 Dysfunction Leads to Disease
Altered SRSF2 function contributes to the development and progression of myeloid neoplasms by disrupting normal RNA splicing. Mutations in SRSF2 can change its ability to bind to specific RNA sequences. This altered binding affinity leads to mis-splicing of hundreds of other genes, resulting in the incorrect inclusion or exclusion of exons.
This mis-splicing can produce faulty proteins or alter the levels of correctly made proteins, which then disrupts normal cellular processes like cell growth, differentiation, and programmed cell death. For instance, some SRSF2 mutations can inhibit cell proliferation by inducing cell cycle arrest and apoptosis. The distorted cell cycle can prevent cells from completing their division and lead to cell death. This disruption of normal cell regulation mechanisms can drive the uncontrolled cell growth characteristic of cancer development.