Alternative titles; symbols
HGNC Approved Gene Symbol: SRSF3
Cytogenetic location: 6p21.31-p21.2 Genomic coordinates (GRCh38): 6:36,594,362-36,605,600 (from NCBI)
SRSF3 is an RNA-binding protein essential for megakaryocyte (MK) maturation and platelet production (Heazlewood et al., 2022).
The SR family of mRNA splicing factors was so designated because SR proteins contain sequences of consecutive serine (S) and arginine (R) dipeptides. Zahler et al. (1992) identified 6 SR proteins in HeLa cell extracts, and named them SRp30a (600812), SRp30b (600813), SRp40 (600914), SRp20, SRp55 (601944), and SRp75 (601940), based on their apparent molecular masses. By searching a sequence database with the partial protein sequence of SRp20, the authors found that a previously identified cDNA, X16, encoded mouse SRp20. Using PCR with primers based on the X16 sequence, they cloned a HeLa cell cDNA encoding human SRp20. The predicted 164-amino acid mouse and human proteins are identical. The sequence of the SRp20 protein is related to those of the other SR proteins identified; all contain 1 or 2 copies of an N-terminal repeat (A and B) spaced by a series of glycine residues that may form a flexible hinge, followed by a C-terminal SR domain. The A repeat contains an RNA recognition motif (RRM). SRp20 and SRp30b contain repeat A only. Zahler et al. (1992) reported that all animal cells tested expressed at least 6 SR proteins. They suggested that SR proteins have different specificities for subclasses of pre-mRNAs and that regulation of the levels of SR proteins in different cell types contributes to the regulation of cell-specific splice choices.
Jumaa et al. (1997) found that the mouse SRp20 gene contains 6 exons and an additional alternative exon.
Gross (2022) mapped the SRSF3 gene to chromosome 6p21.31-p21.2 based on an alignment of the SRSF3 sequence (GenBank BC069018) with the genomic sequence (GRCh38).
By interspecific backcross analysis, Jumaa et al. (1997) mapped the mouse SRp20 gene to a 2-centimorgan interval on chromosome 17.
Lou et al. (1998) demonstrated that SRp20 affected the recognition of an alternative 3-prime-terminal exon via an effect on the efficiency of binding of the 64-kD subunit of CSTF (300907), a polyadenylation factor, to an alternative polyadenylation site. They suggested that SR proteins can influence pre-mRNA processing at the level of polyadenylation and generally participate in terminal exon recognition.
Jumaa et al. (1997) demonstrated that in vivo, SRp20 mRNA levels are cell cycle regulated and that the SRp20 mRNA is itself alternatively spliced, apparently in a cell cycle-specific manner. Sequence analysis revealed that the SRp20 promoter contains 2 consensus binding sites for E2F (189971), a transcription factor thought to be involved in regulating the cell cycle. The authors suggested that cellular pre-mRNA splicing may be regulated during the cell cycle, perhaps in part by regulated expression of SR proteins.
Lareau et al. (2007) reported that in every member of the human SR family of splicing regulators, highly or ultraconserved elements are alternatively spliced, either as alternative 'poison cassette exons' containing early in-frame stop codons, or as alternative introns in the 3-prime untranslated region. These alternative splicing events target the resulting mRNAs for degradation by means of an RNA surveillance pathway called nonsense-mediated mRNA decay. Mouse orthologs of the human SR proteins exhibit the same unproductive splicing patterns. Three SR proteins, SRp20, SC35 (600813), and 9G8 (SFRS7; 600572), had been previously shown to direct splicing of their own transcripts, and SC35 autoregulates its expression by coupling alternative splicing with decay. Lareau et al. (2007) concluded that unproductive splicing is important for regulation of the entire SR family and found that unproductive splicing associated with conserved regions has arisen independently in different SR genes, suggesting that splicing factors may readily acquire this form of regulation.
Heazlewood et al. (2022) noted that systemic knockout of Srsf3 in mice is lethal at the morula stage. Heazlewood et al. (2022) found that Srsf3 +/- mice were born in the expected numbers, but about half died before weaning. Surviving Srsf3 +/- mice were anatomically and morphologically normal and had close to normal levels of Srsf3 protein and mRNA in examined tissues. However, Srsf3 +/- mice had reduced platelet counts without a decrease in bone marrow MKs. Mice homozygous for MK-specific Srsf3 deletion were viable and fertile with the expected number of offspring. However, Srsf3 ablation in MKs resulted in severe thrombocytopenia without a change in MK numbers. Ultrastructural analysis revealed that, following a maturation arrest, Srsf3-deficient MKs released abnormally large platelets, a characteristic of human macrothrombocytopenias, in addition to having reduced platelet counts. The abnormal platelets were correctly primed for activation, but their function was compromised, and they were rapidly cleared from circulation. Analysis of the RNA repertoire showed that Srsf3 was critical for RNA regulation during MK maturation and platelet release, as Srsf3-deficient MKs failed to reprogram their transcriptome during maturation and sort functionally important RNAs into platelets.
Gross, M. B. Personal Communication. Baltimore, Md. 8/26/2022.
Heazlewood, S. Y., Ahmad, T., Mohenska, M., Guo, B. B., Gangatirkar, P., Josefsson, E. C., Ellis, S. L., Ratnadiwakara, M., Cao, H., Cao, B., Heazlewood, C. K., Williams, B., Fulton, M., White, J. F., Ramialison, M., Nilsson, S. K., Anko, M. L. The RNA-binding protein SRSF3 has an essential role in megakaryocyte maturation and platelet production. Blood 139: 1359-1373, 2022. [PubMed: 34852174] [Full Text: https://doi.org/10.1182/blood.2021013826]
Jumaa, H., Guenet, J.-L., Nielsen, P. J. Regulated expression and RNA processing of transcripts from the Srp20 splicing factor gene during the cell cycle. Molec. Cell. Biol. 17: 3116-3124, 1997. [PubMed: 9154810] [Full Text: https://doi.org/10.1128/MCB.17.6.3116]
Lareau, L. F., Inada, M., Green, R. E., Wengrod, J. C., Brenner, S. E. Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements. Nature 446: 926-929, 2007. [PubMed: 17361132] [Full Text: https://doi.org/10.1038/nature05676]
Lou, H., Neugebauer, K. M., Gagel, R. F., Berget, S. M. Regulation of alternative polyadenylation by U1 snRNPs and SRp20. Molec. Cell. Biol. 18: 4977-4985, 1998. [PubMed: 9710581] [Full Text: https://doi.org/10.1128/MCB.18.9.4977]
Zahler, A. M., Lane, W. S., Stolk, J. A., Roth, M. B. SR proteins: a conserved family of pre-mRNA splicing factors. Genes Dev. 6: 837-847, 1992. [PubMed: 1577277] [Full Text: https://doi.org/10.1101/gad.6.5.837]