SKA2

Spindle and kinetochore-associated protein 2 is a protein that in humans is encoded by the SKA2 gene found in chromosome 17. SKA2 is a part of a spindle and kinetochore associated complex also including SKA1 and SKA3 which is responsible for onset of the anaphase in mitosis by regulating chromosomal segregation.[1][2]

SKA2
Identifiers
Aliases
External IDsGeneCards:
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human
Spindle and Kinetochore Associated Complex Subunit 2
Identifiers
SymbolSKA2
Alt. namesFamily with Sequence Similarity 33. Member A, FAM33A, Spindle and KT (Kinetochore) Associated 2, Protein FAM33A
NCBI gene348235
HGNC28006
OMIM616674
UniProtQ8WVK7
Other data
LocusChr. 17 q22
Search for
StructuresSwiss-model
DomainsInterPro

SKA2 may function as a prognostic gene marker for identifying lung cancer[3] as well as a proposed biomarker for suicidal tendencies and post-traumatic stress disorders.[4][5] The SKA2 gene contains one single-nucleotide polymorphism (SNP) rs7208505 located in the 3' UTR. This genetic variant containing a cytosine (existing in the less common allele) instead of thymine along with epigenetic modification (such as DNA methylation) is correlated with suicidal tendencies and post-traumatic stress.[4]

Discovery

SKA2 protein was first documented as a product of as hypothetical gene FAM33A part of a Spindle and Kinetochore (KT)- associated complex necessary for timely anaphase onset. SKA2 was identified as the partner of SKA1, hence the name in 2006.[2] Later on the 3rd component of the SKA complex was mass spectrometrically identified as C13Orf3 later referred to as SKA3.[6] This complex plays an important role in the cell during mitotic transition from the metaphase to the anaphase.[2]

Protein structure and sub-cellular localization

SKA2 gene product is a 121 amino acid long chain and a molecular weight of 14,188 Da containing mainly 3 helices.[7] Homologues of SKA2 protein being very small are found in several vertebrates but absent in invertebrates.[2] This protein mainly localizes in the condensed chromosome and to the outer spindle and kinetochore microtubules during mitosis.[2] The SKA2 proteins localizes to the mitotic spindle and kinetochore associated proteins such as SKA1 and SKA3.[8]

Function

The SKA2 is a part of the larger spindle and kinetochore complex which is a sub-complex of the outer kinetochore and binds to the microtubules.[2][8][9] This complex is essential for the correctly timed onset of anaphase during mitosis by helping in the chromosomal segregation[2] and aids in the movement of microspheres along a microtubule in a depolymerisation-coupled manner, since it is a direct component in the kinetochore-microtubule interface along with directly associating with the microtubules as assemblies.[9]

A reduced expression of SKA2 results in the loss of the complex from the kinetochore, however this loss of SKA-complex does not affect the overall structure of the Kinetochore yet the fibres show increased cold-sensitivity due to the loss. The cell goes through a prolonged delay in a metaphase-like state.[2] It has been concluded that SKA2 regulates the maintenance of the metaphase plate and silencing of the spindle checkpoint leading to the onset of anaphase during mitosis.[2] SKA2 also interacts with the glucocorticoid receptor aiding in the chaperoning of the receptor in the nucleus.[10]

Clinical significance

Suicidal tendencies and post-traumatic stress disorder

The DNA methylation of SKA2 gene and the Single-nucleotide polymorphism rs7208505 genotype may have effects on suicidal behaviour according to linear model suggested by a study in 2014. The genotype rs7208505 contains a single nucleotide polymorphism (SNP) containing a Cytosine variant allele instead of Thymine present in the common allele. This SNP allows the dinucleotide repeat (CpG) elements to occur providing a gene segment for methylation. Thus DNA methylation alone may be the primary factor conferring risk of suicidal behaviour. A study of allele of rs7208505 in different ethnic groups along with numerous psychiatric diagnosis suggested that the variation in SKA2 may mediate risk for suicidal behaviours that progress to attempt to suicide.[4]

Lung cancer

The SKA2 gene along with PRR11 gene as a pair is essential for the development of lung cancer. The pair of genes are separated by a 548 bp intergenic region, and having a classical head-to-head gene pair motif share a prototypical bidirectional promoter containing a common CCAAT element.[11][12] This promoter is regulated by NF-Y is a sequence specific transcription factor and has long been considered an activator of genes since it contains particular properties suitable to regulate bidirectional promotor with the CCAAT box sequence. This bidirectional promoters couple expression of 2 genes (protein coding) involved in the same biochemical process to allow a synchronized temporal or environmental control. The 2 genes SKA2 and PRR11 are vital for accelerated growth and motility of lung cancer cells and have prognostic value for patients. Along with SKA2, PRR11 also plays a major role in regulating cell cycle progression but from the late S phase to mitosis.[2][13] Thus, having vital roles to play in cell cycle progression at different stages, SKA2 and PRR11 may co-ordinately regulate lung cancer proliferation by deregulation of cell cycle progression.[3] Since the transcription of SKA2 gene produces the protein coding mRNA SKA2 along with 2 other introns miRNA301a and miRNAA454, hence the function of the gene is not limited to production of a protein.[3] These introns participate in tumorigenesis since miRNA301a regulates PTEN, NKRF, SMAD4 and PIAS3 and miRNAA454 targets SMAD4 playing an oncogenic role in human colon cancer.[14]

Interactions

References
  1. "SKA2". Entrez Gene. Retrieved 3 Aug 2014.
  2. Hanisch A, Silljé HH, Nigg EA (November 2006). "Timely anaphase onset requires a novel spindle and kinetochore complex comprising Ska1 and Ska2". The EMBO Journal. 25 (23): 5504–15. doi:10.1038/sj.emboj.7601426. PMC 1679759. PMID 17093495.
  3. Wang Y, Zhang Y, Zhang C, Weng H, Li Y, Cai W, Xie M, Long Y, Ai Q, Liu Z, Du G, Wang S, Niu Y, Song F, Ozaki T, Bu Y (September 2015). "The gene pair PRR11 and SKA2 shares a NF-Y-regulated bidirectional promoter and contributes to lung cancer development". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1849 (9): 1133–44. doi:10.1016/j.bbagrm.2015.07.002. PMID 26162986.
  4. Guintivano J, Brown T, Newcomer A, Jones M, Cox O, Maher BS, Eaton WW, Payne JL, Wilcox HC, Kaminsky ZA (December 2014). "Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors". The American Journal of Psychiatry. 171 (12): 1287–96. doi:10.1176/appi.ajp.2014.14010008. PMC 7081376. PMID 25073599. S2CID 46235766.
  5. "Prototype blood test will assess for suicide risk in soldiers". The Independent (UK). 3 Aug 2014. Retrieved 3 Aug 2014.
  6. Gaitanos TN, Santamaria A, Jeyaprakash AA, Wang B, Conti E, Nigg EA (May 2009). "Stable kinetochore-microtubule interactions depend on the Ska complex and its new component Ska3/C13Orf3". The EMBO Journal. 28 (10): 1442–52. doi:10.1038/emboj.2009.96. PMC 2669960. PMID 19360002.
  7. Jeyaprakash AA, Santamaria A, Jayachandran U, Chan YW, Benda C, Nigg EA, Conti E (May 2012). "Structural and functional organization of the Ska complex, a key component of the kinetochore-microtubule interface". Molecular Cell. 46 (3): 274–86. doi:10.1016/j.molcel.2012.03.005. PMID 22483620.
  8. Welburn JP, Grishchuk EL, Backer CB, Wilson-Kubalek EM, Yates JR, Cheeseman IM (March 2009). "The human kinetochore Ska1 complex facilitates microtubule depolymerization-coupled motility". Developmental Cell. 16 (3): 374–85. doi:10.1016/j.devcel.2009.01.011. PMC 2746561. PMID 19289083.
  9. Schmidt JC, Arthanari H, Boeszoermenyi A, Dashkevich NM, Wilson-Kubalek EM, Monnier N, Markus M, Oberer M, Milligan RA, Bathe M, Wagner G, Grishchuk EL, Cheeseman IM (November 2012). "The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments". Developmental Cell. 23 (5): 968–80. doi:10.1016/j.devcel.2012.09.012. PMC 3500403. PMID 23085020.
  10. Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P, Blackhall FH, Zeef L, Telfer B, Stratford I, Clarke R, Singh D, Stevens A, White A, Ray DW (September 2008). "Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor". The Journal of Endocrinology. 198 (3): 499–509. doi:10.1677/joe-08-0019. PMC 2518725. PMID 18583474.
  11. Wakano C, Byun JS, Di LJ, Gardner K (July 2012). "The dual lives of bidirectional promoters". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1819 (7): 688–93. doi:10.1016/j.bbagrm.2012.02.006. PMC 3371153. PMID 22366276.
  12. Orekhova AS, Rubtsov PM (April 2013). "Bidirectional promoters in the transcription of mammalian genomes". Biochemistry. Biokhimiia. 78 (4): 335–41. doi:10.1134/S0006297913040020. PMID 23590436. S2CID 18378130.
  13. Zhang C, Zhang Y, Li Y, Zhu H, Wang Y, Cai W, Zhu J, Ozaki T, Bu Y (March 2015). "PRR11 regulates late-S to G2/M phase progression and induces premature chromatin condensation (PCC)". Biochemical and Biophysical Research Communications. 458 (3): 501–8. doi:10.1016/j.bbrc.2015.01.139. PMID 25666944.
  14. Liu L, Nie J, Chen L, Dong G, Du X, Wu X, Tang Y, Han W (5 February 2013). "The oncogenic role of microRNA-130a/301a/454 in human colorectal cancer via targeting Smad4 expression". PLOS ONE. 8 (2): e55532. Bibcode:2013PLoSO...855532L. doi:10.1371/journal.pone.0055532. PMC 3564758. PMID 23393589.
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