The Serine/Arginine Repetitive Matrix 2 protein (SRRM2) is a fundamental component of gene expression in human cells. Classified as a splicing factor, SRRM2 is required for pre-messenger RNA (pre-mRNA) splicing, a process where genetic information is edited to create a final, usable message. Disruptions in the gene’s activity are directly linked to cellular health and have been implicated across a spectrum of human illnesses.
Understanding RNA Splicing
Genetic information flows from DNA to RNA and finally to protein. The DNA blueprint is first copied into a precursor RNA molecule containing both coding and non-coding segments. Before the cell can use these instructions, the precursor RNA must undergo a precise editing process called RNA splicing.
This cellular editing involves removing non-coding regions, known as introns, and joining the coding sequences, called exons. The result is a mature messenger RNA (mRNA) molecule that carries a continuous code ready for protein synthesis.
This intricate process is carried out by the spliceosome, a large molecular machine composed of five small nuclear RNAs and numerous associated proteins. The spliceosome recognizes specific sequence boundaries on the pre-mRNA and catalyzes chemical reactions that cut the intron out and ligate the flanking exons. Splicing occurs in the nucleus and is a post-transcriptional modification necessary for creating functional mRNA in eukaryotic cells.
SRRM2’s Regulatory Role
SRRM2 functions as a molecular organizer that dictates how splicing occurs. It belongs to the SR-related family of proteins and acts as a scaffold to help assemble the splicing machinery. The protein is a primary component of nuclear speckles, dynamic structures within the nucleus where splicing factors are stored.
SRRM2 organizes these nuclear speckles by forming biomolecular condensates, a process driven by its intrinsically disordered regions (IDRs). This ability to form liquid-like droplets concentrates the necessary splicing components at the correct location. SRRM2 regulates alternative splicing, which allows a single gene to encode multiple distinct protein products.
Alternative splicing is a major source of biological complexity, generating thousands of different proteins from a limited number of genes. SRRM2 deficiency often induces the skipping of certain cassette exons, especially those with short introns and weak splice sites. By controlling which exons are included or excluded from the final mRNA, SRRM2 determines the structure and function of the resulting protein, influencing cellular diversity.
SRRM2 and Human Disease Links
Disruption or misregulation of SRRM2’s regulatory control can lead to various diseases, as errors in alternative splicing patterns link the gene directly to human pathology. Specific loss-of-function variants in the SRRM2 gene have been identified as a cause of neurodevelopmental disorders.
These genetic alterations result in conditions characterized by mild developmental delay, intellectual disability, and speech difficulties. SRRM2 dysregulation is also evident in neurodegenerative diseases. For example, in Alzheimer’s disease, phosphorylated SRRM2 protein is mislocalized and accumulates in the cytoplasm of neurons, correlating with the severity of pathological tau deposition.
In cancer, misregulation of SRRM2-mediated alternative splicing can promote tumor growth by altering the protein isoforms produced. SRRM2 depletion in acute myeloid leukemia changes splice variants of target genes like MUC1 and FES, promoting oncogenic properties. Furthermore, a specific S346F mutation in SRRM2 has been linked to a predisposition for papillary thyroid carcinoma. SRRM2 is also exposed on the surface of various cancer cells, positioning it as a promising target for immunotherapy, such as specialized CAR-T cell therapies.