SKA2

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SKA2
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SpeciesHumanMouse
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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 gene 348235
HGNC 28006
OMIM 616674
UniProt Q8WVK7
Other data
Locus Chr. 17 q22

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]

Contents

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

Related Research Articles

Mitosis The division of a cell nucleus in which the genome is copied and separated into two identical halves

In cell biology, mitosis is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. Therefore, the mitosis is also known as equational division. In general, mitosis is preceded by the S stage of interphase and is often followed by telophase and cytokinesis; which divides the cytoplasm, organelles and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of Mitosis altogether define the mitotic (M) phase of an animal cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

Anaphase Stage of a cell division

Anaphase, is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes are moved to opposite poles of the cell. Chromosomes also reach their overall maximum condensation in late anaphase, to help chromosome segregation and the re-formation of the nucleus.

Spindle apparatus Array of microtubules and associated molecules that forms between opposite poles of a eukaryotic cell during mitosis or meiosis and serves to move the duplicated chromosomes apart

In cell biology, the spindle apparatus refers to the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

Cyclin

Cyclin is a family of proteins that controls the progression of a cell through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes or group of enzymes required for synthesis of cell cycle.

Spindle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

Kinetochore Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. Its proteins also help to hold the sister chromatids together and play a role in chromosome editing. Details of the specific areas of origin are unknown.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

Aurora B kinase Protein

Aurora B kinase is a protein that functions in the attachment of the mitotic spindle to the centromere.

Anaphase lag is a consequence of an event during cell division where sister chromatids do not properly separate from each other because of improper spindle formation. The chromosome or chromatid does not properly migrate during anaphase and the daughter cells will lose some genetic information. It is one of many causes of aneuploidy. This event can occur during both meiosis and mitosis with unique repercussions. In either case, anaphase lag will cause one daughter cell to receive a complete set of chromosomes while the other lacks one paired set of chromosomes, creating a form of monosomy. Whether the cell survives depends on which sister chromatid was lost and the background genomic state of the cell. The passage of abnormal numbers of chromosomes will have unique consequences with regards to mosaicism and development as well as the progression and heterogeneity of cancers.

PLK1

Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.

CDC20

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

BUB1

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.

BUB1B

Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene.

CDC27

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

CENPF Centromere- and microtubule-associated protein

Centromere protein F is a protein that in humans is encoded by the CENPF gene. It is involved in chromosome segregation during cell division. It also has a role in the orientation of microtubules to form cellular cilia.

CDC16

Cell division cycle protein 16 homolog is a protein that in humans is encoded by the CDC16 gene.

BUB3

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

AURKC

Serine/threonine-protein kinase 13 is an enzyme that in humans is encoded by the AURKC gene.

Mad1

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologs of Mad1 are conserved in eukaryotes from yeast to mammals.

J. Richard McIntosh is a Distinguished Professor Emeritus in Molecular, Cellular, and Developmental Biology at the University of Colorado Boulder. McIntosh first graduated from Harvard with a BA in Physics in 1961, and again with a Ph.D. in Biophysics in 1968. He began his teaching career at Harvard but has spent most of his career at the University of Colorado Boulder. At the University of Colorado Boulder, McIntosh taught biology courses at both the undergraduate and graduate levels. Additionally, he created an undergraduate course in the biology of cancer towards the last several years of his teaching career. McIntosh's research career looks at a variety of things, including different parts of mitosis, microtubules, and motor proteins.

References

  1. ↑ "SKA2". Entrez Gene . Retrieved 3 Aug 2014.
  2. 1 2 3 4 5 6 7 8 9 10 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. 1 2 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. 1 2 3 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. 1 2 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. 1 2 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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