SRSF2 UniProt Q01130

1 alternative isoform · canonical 221 aa · nucleus; nucleoplasm

SRSF2 (SC35) is an essential SR-family pre-mRNA splicing factor that recognizes degenerate exonic splicing enhancers through its RRM and promotes spliceosome assembly, splice-site selection, and exon inclusion across many tissue-specific programs [PMID:1373910, PMID:1454802]. It was originally isolated as a factor required for the first step of splicing and for spliceosome assembly, reconstituting splicing activity in S100 and immunodepleted extracts where it favors proximal splice sites in antagonism with hnRNP A1 [PMID:1373910, PMID:1454802], and it can substitute for U2AF65 to recruit U2 snRNP in a substrate-specific, U1 snRNP-dependent manner [PMID:8990173]. Sequence-specificity studies and solution NMR structures of the RRM define a high-affinity 5'-SSNG-3' consensus, with the protein binding 5'-UCCAGU-3' and 5'-UGGAGU-3' equally by flipping central C or G bases between anti and syn conformations and with the elongated L3 loop essential for RNA contact [PMID:10629063, PMID:22002536, PMID:22140111]; the RRM also serves as a reader of m5C-modified mRNA, with NSUN2-deposited m5C enhancing SRSF2 binding [PMID:38065062]. Beyond splicing, SRSF2 facilitates transcriptional elongation by promoting P-TEFb recruitment and CTD Ser2 phosphorylation [PMID:18641664] and autoregulates its own expression through alternative splicing of its terminal exon coupled to mRNA surveillance [PMID:11285241, PMID:19965769]. Its activity is tuned by post-translational control, including Tip60-mediated K52 acetylation that drives proteasomal degradation and HDAC6/SRPK opposition [PMID:21157427]. Genetically, SRSF2 is required for T cell maturation, cardiac and hepatic homeostasis, and myogenesis, regulating defined targets such as CD45, RyR2, and stress-death pathway genes [PMID:11239462, PMID:14963485, PMID:27022105, PMID:35460187]. Recurrent Pro95 hot-spot mutations (e.g., P95H) cause myelodysplastic/myeloproliferative neoplasms by shifting RNA-binding specificity toward UCCAG over UGGAG motifs, mis-splicing hematopoietic regulators including EZH2 and HNRNPA2B1, enhancing EJC-dependent nonsense-mediated decay, impairing m5C reading, and disrupting mitochondrial mRNA splicing such that PINK1-mediated mitophagy becomes essential for mutant-cell survival [PMID:25965569, PMID:26261309, PMID:29858584, PMID:32001512, PMID:38065062, PMID:38713535].