SRSF2
Primary Author(s)*
Paul De Fazio, MSc, Monash Health
Synonyms
- Splicing Factor, Arginine/Serine-Rich 2
- Serine And Arginine Rich Splicing Factor 2
- Splicing Component, 35 KDa
- Splicing Factor SC35
- SC35
Genomic Location
Cytoband: 17q25.1
Genomic Coordinates:
chr17:74,730,197-74,733,493 [hg19]
chr17:76,734,115-76,737,629 [hg38]
Cancer Category/Type
Myelodysplastic Syndromes (MDS)
SRSF2 is mutated in approximately 14% of MDS patients (Papaemmanuil et al., 2013). SRSF2 variants are mutually exclusive to EZH2 variants, SF3B1 variants, and pathogenic variants in other splicing factors, but are positively correlated with IDH1, IDH2, and RUNX1 mutations (Papaemmanuil et al., 2013; Thol et al., 2012; Yoshida et al., 2011). SRSF2 variants typically originate early in the generation of dysplastic lineages (Papaemmanuil et al., 2013). SRSF2 variants correlate with shorter overall survival and more frequent progression to acute myeloid leukemia (AML) (Thol et al., 2012). These variants are almost always missense mutations in proline residue 95 (NM_003016.4) (Yoshida et al., 2011).
Chronic Myelomonocytic Leukemia (CMML)
SRSF2 variants, predominantly missense mutations affecting the proline 95 (NM_003016.4) residue, are seen in approximately 32-47% of chronic myelomonocytic leukemia (CMML) cases but rarely in juvenile myelomonocytic leukemia (Kar et al., 2013; Meggendorfer et al., 2012). SRSF2 variants are positively correlated with higher age, less pronounced anemia, and a normal karyotype. The prognostic impact is unclear, although SRSF2 and RUNX1 co-mutation may correlate with an improved overall survival (Itzykson et al., 2013; Meggendorfer et al., 2012). EZH2 and SRSF2 variants are mutually exclusive (Meggendorfer et al., 2012).
Acute Myeloid Leukemia (AML) and Related Precursor Neoplasms
Mutations in SRSF2, mostly affecting proline 95 (NM_003016.4), are found in ~7% of acute myeloid leukemia (AML) with myelodysplasia-related changes but rarely (<1%) in patients with de novo AML (Yoshida et al., 2011). One study found that SRSF2 variants correlated with older age but no other prognostic markers in AML; however, AML sub-types were not separated (Yang et al., 2016).
Gene Overview
SRSF2 is a member of the SR superfamily of proteins defined by an Arginine/Serine-rich domain (or RS domain) at their C terminus and invariably an N-terminal RNA recognition motif (Zhou and Fu, 2013). SRSF2 and other SR family members are able to auto- and cross-regulate themselves through ‘unproductive splicing’ (Lareau et al., 2007). The SR proteins are functionally distinct (Zahler et al., 1993). Unlike other SR proteins which are shuttled in and out of the nucleus continuously, SRSF2 remains exclusively in the nucleus (Cáceres et al., 1998).
SRSF2 is involved in constitutive splicing (Fu and Maniatis, 1990) by promoting U1 snRNP binding to the 5’ splice site and U2 snRNP binding to the 3’ splice site of immature mRNA, and facilitating spliceosome recruitment, the latter of which requires SR phosphorylation (Fu and Maniatis, 1992; Roscigno and Garcia-Blanco, 1995).
Acetylation and phosphorylation are important regulatory modifications of SR family proteins (reviewed in Zhou and Fu, 2013). SRSF2 specifically is acetylated by TIP60 and deacetylated by HDAC6 on lysine residue 52, which mediates its RNA-binding and proteasomal degradation; treatment of cells with cisplatin inhibits TIP60 and therefore stabilises SRSF2 (Edmond et al., 2011). Phosphorylation occurs primarily through SR-protein specific kinases (SRPKs) and CDC-2 like kinases (CLKs), which function symbiotically in phosphorylating and dephosphorylating SR proteins at the SR domain (Aubol et al., 2016). This function appears to be necessary for spliceosome progression from assembly to catalysis and, in SR proteins other than SRSF2, for intracellular trafficking (reviewed in Zhou and Fu, 2013). The AKT-SRPK-SR protein axis is a major pathway for EGF signalling to regulate alternative splicing, whereby activated AKT enhances SRPK nuclear localisation with involvement from heat shock proteins Hsp70 and Hsp90 and 14-3-3 proteins (Zhou et al., 2012). SR protein function is also regulated by their competition with heterogeneous nuclear ribonucleoproteins (hnRNPs) for RNA binding (Lin and Fu, 2007).
SR proteins are essential for development in a tissue specific manner, with SRSF2 in particular playing roles in heart development, T-cell development through alternative splicing of CD45, and haematopoiesis (Ding et al., 2004; Komeno et al., 2015; Wang et al., 2001). In angiogenesis SRSF2 promotes the alternative splicing of an anti-angiogenic form of vascular endothelial growth factor (VEGF) (Merdzhanova et al., 2010). In cancer, SRSF2 variants have been implicated in leukemia and myeloid disorders (Meggendorfer et al., 2012; Yoshida et al., 2011). These variants, predominantly affecting proline residue 95 (NM_003016.4), alter splicing of SRSF2 targets by impairing RNA binding, likely explaining their pathogenicity (Kim et al., 2015; Zhang et al., 2015). SRSF2 mutations are associated with age-related clonal hematopoiesis (Mason et al., 2016; McKerrell et al., 2015).
Common Alteration Types
SRSF2 variants almost exclusively affect proline residue 95 (NM_003016.4), which lies between the RNA-binding and RS domains.
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X |
Internal Pages
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External Links
SRSF2 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
SRSF2 by COSMIC - sequence information, expression, catalogue of mutations
SRSF2 by CIViC - general knowledge and evidence-based variant specific information
SRSF2 by St. Jude ProteinPaint mutational landscape and matched expression data.
SRSF2 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
SRSF2 by Cancer Index - gene, pathway, publication information matched to cancer type
SRSF2 by OncoKB - mutational landscape, mutation effect, variant classification
SRSF2 by My Cancer Genome - brief gene overview
SRSF2 by UniProt - protein and molecular structure and function
SRSF2 by Pfam - gene and protein structure and function information
SRSF2 by GeneCards - general gene information and summaries
References
EXAMPLE Book
- Arber DA, et al., (2008). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, Editors. IARC Press: Lyon, France, p117-118.
EXAMPLE Journal Article
- Li Y, et al., (2001). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28:220-221, PMID 11431691.
Notes
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