Alternative titles; symbols
HGNC Approved Gene Symbol: SRPK2
Cytogenetic location: 7q22.3 Genomic coordinates (GRCh38): 7:105,114,740-105,399,357 (from NCBI)
Pre-mRNA splicing is a critical step in the posttranscriptional regulation of gene expression. This process requires small nuclear ribonucleoprotein particles (snRNPs) and non-snRNP splicing factors, both of which are stored in nuclear 'speckles.' Non-snRNP factors containing an arginine/serine-rich (RS) domain, designated 'SR proteins' (e.g., SFRS1, 600812), are phosphorylated, predominantly on serines within their RS domains. By RT-PCR using degenerate oligonucleotides based on amino acid sequences conserved between human SRPK1 (601939) and S. pombe Dsk1, Kuroyanagi et al. (1998) isolated mouse brain cDNAs encoding Srpk2. Northern blot analysis detected tissue-specific expression of several Srpk2 transcripts in mouse brain, lung, and testis. The predicted Srpk2 protein contains conserved serine/threonine kinase domains, a proline-rich domain, a basic region which may be a nuclear localization signal, and an acidic domain. The mouse Srpk2 protein is 58% and 32% identical to the human SRPK1 and yeast Dsk1 proteins, respectively. The authors demonstrated that Srpk2 phosphorylated ASF/SF2 (SFRS1) in vitro. Overexpression of Srpk2 caused the disassembly of nuclear 'speckles' containing recombinant ASF/SF2 or endogenous SC35 (SFRS2; 600813).
Wang et al. (1998) cloned human SRPK2 from a fetal brain cDNA library and found that it encodes a deduced 686-amino acid protein.
Using a somatic cell hybrid mapping panel and FISH, Wang et al. (1999) mapped the SRPK2 gene to 7q22-q31. They mapped the mouse Srpk2 gene to chromosome 5.
Mathew et al. (2008) demonstrated that SRPK1 copurifies predominantly with the U1 snRNP, whereas SRPK2 copurifies solely with the tri-snRNP. RNAi-mediated depletion in HeLa cells showed that SRPK2 is essential for cell viability, and that it is required for spliceosomal B complex formation. SRPK2 knockdown resulted in hypophosphorylation of PRP28 (DDX23; 612172) and destabilized PRP28 association with the tri-snRNP. Immunodepletion of PRP28 from HeLa cell nuclear extract and complementation studies revealed that PRP28 phosphorylation is required for its stable association with the tri-snRNP and for tri-snRNP integration into the B complex.
By knockdown analysis in U2OS human osteosarcoma cells and HeLa cells, Sridhara et al. (2017) found that SRPK2 was necessary to protect against accumulation of R-loops and to prevent RNA-mediated genomic instability. Similarly, loss of DDX23 triggered genomic instability and was frequent in adenoid cystic carcinoma. Expression of phosphomimetic DDX23 restored genome integrity in SRPK2-depleted cells. Restoration of genome integrity by DDX23 was RNA dependent, as R-loops were the source of DNA damage in DDX23-deficient cells, and restoration required DDX23 RNA helicase activity. DDX23 was directly recruited to chromatin regions containing R-loops, and SPRK2-mediated phosphorylation of DDX23 was required for R-loop suppression.
Kuroyanagi, N., Onogi, H., Wakabayashi, T., Hagiwara, M. Novel SR-protein-specific kinase, SRPK2, disassembles nuclear speckles. Biochem. Biophys. Res. Commun. 242: 357-364, 1998. [PubMed: 9446799] [Full Text: https://doi.org/10.1006/bbrc.1997.7913]
Mathew, R., Hartmuth, K., Mohlmann, S., Urlaub, H., Ficner, R., Luhrmann, R. Phosphorylation of human PRP28 by SRPK2 is required for integration of the U4/U6-U5 tri-snRNP into the spliceosome. Nature Struct. Molec. Biol. 15: 435-443, 2008. [PubMed: 18425142] [Full Text: https://doi.org/10.1038/nsmb.1415]
Sridhara, S. C., Carvalho, S., Grosso, A. R., Gallego-Paez, L. M., Carmo-Fonseca, M., Fernandes de Almeida, S. Transcription dynamics prevent RNA-mediated genomic instability through SRPK2-dependent DDX23 phosphorylation. Cell Rep. 18: 334-343, 2017. [PubMed: 28076779] [Full Text: https://doi.org/10.1016/j.celrep.2016.12.050]
Wang, H. Y., Arden, K. C., Bermingham, J. R., Jr., Viars, C. S., Lin, W., Boyer, A. D., Fu, X. D. Localization of serine kinases, SRPK1 (SFRSK1) and SRPK2 (SFRSK2), specific for the SR family of splicing factors in mouse and human chromosomes. Genomics 57: 310-315, 1999. [PubMed: 10198174] [Full Text: https://doi.org/10.1006/geno.1999.5770]
Wang, H. Y., Lin, W., Dyck, J. A., Yeakley, J. M., Songyang, Z., Cantley, L. C., Fu, X. D. SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. J. Cell Biol. 140: 737-750, 1998. [PubMed: 9472028] [Full Text: https://doi.org/10.1083/jcb.140.4.737]