Wikipedia

Cyclin B3

G2/mitotic-specific cyclin-B3 is a protein encoded by the CCNB3 gene located on the X chromosome in humans.[5] Cyclin B3 has features of both A type cyclins and B type cyclins and is a distinct subfamily of B type cyclins conserved across many species.[6][7][8][9] However, human cyclin B3 is considerably larger than all other previously characterized invertebrate or vertebrate cyclin B3s.[10] Unlike cyclin B1 and cyclin B2, it is solely expressed in germ cells in mammals, with a significant role in meiosis and gamete formation.[11]

CCNB3
Identifiers
AliasesCCNB3, cyclin B3, CYCB3
External IDsOMIM: 300456; MGI: 2183443; HomoloGene: 13199; GeneCards: CCNB3; OMA:CCNB3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

85417

209091

Ensembl

ENSG00000147082

ENSMUSG00000051592

UniProt

Q8WWL7

Q810T2

RefSeq (mRNA)

NM_033031
NM_033670
NM_033671

NM_183015

RefSeq (protein)

NP_149020
NP_391990

NP_898836

Location (UCSC)Chr X: 50.2 – 50.35 MbChr X: 6.85 – 6.91 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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Cyclin B3 was originally identified in chickens from cDNA as a 403 amino acid protein. It has roughly 30% similarity to chicken and Xenopus B and A type cyclins. The cyclin box of chicken cyclin B3 has 15 residues different from the consensus sequence for B type cyclins and 22 residues different from the consensus sequence for A type cyclins. The destruction box sequence for chicken cyclin B3 also differs from the expected sequence: it contains a phenylalanine rather than a leucine. The nuclear localization sequence (NLS) of chicken cyclin B3 appears to be in the 26 C-terminal residues, consistent with A type cyclins.[6]

Human cyclin B3 is the largest cyclin, 1395 amino acids long, due to large variable domain (contained in exon 8) between the destruction box and cyclin box. There are indications of alternative splicing that alters localization to the cytoplasm.[8][10][12]

Expression

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Cyclin B3 is nearly entirely localized to the nucleus and cycles similarly to other B cyclins in somatic cells.[6][8] In humans it is primarily expressed in germ cells in the testis, somewhat contradictory to its observed function in oocyte meiosis in other organisms.[8][10]

Function

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When it was initially characterized in HeLa cells, human cyclin B3 was found to associate with CDK2 but it did not significantly spur histone H1 kinase activity as is common with other cyclin-CDK complexes. However, further research has shown that cyclin B3 associates with CDK1 rather than CDK2 (as seen with chicken cyclin B3). In HeLa cells, cyclin B3 was observed to degrade during the metaphase-anaphase transition when it had a complete destruction box. Accumulation of cyclin B3 was also shown to induce the beginning of mitosis early and prevent exit from M phase by arresting cells in anaphase.[8]

Role in mitosis

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Cyclin B3 has primarily mitotic functionality in Caenorhabditis elegans where it is primarily localized to the nucleus and is necessary for chromatid separation.[13] Cyclin B3 is especially important in early C. elegans embryos where it again governs chromatid separation as well as kinetochore and microtubule assembly.[14] It additionally appears to drive rapid mitosis in early C. elegans embryos, roughly three times faster than mitosis in adult worms.[15]

Role in meiosis and gamete production

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Oogenesis

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Cyclin B3 has been investigated in the context of oogenesis as its initial mammalian characterization found mRNA expression in fetal ovaries but not adult ovaries.[8] Female mice with null or severe loss of function mutations to both copies of cyclin B3 (Ccnb3-/-) are sterile: most ccnb3-/- oocytes do not form polar bodies. Cyclin B3-CDK1 complexes promote the degradation of Anaphase Promoting Complex/Cyclosome (APC/C) substrates securin and cyclin B1, which potentially leads to the onset of anaphase I. Cyclin B3 is also degraded as the oocyte leaves meiosis I.[9][16]

Cyclin B3-CDK1 complexes also phosphorylate Emi2, an APC/C inhibitor, flagging it for degradation which maintains APC/C activity. Importantly, cyclin B3 is not present during meiosis II, which allows for arrest in metaphase II.[17] This pattern of degradation, different from cyclins B1 and B2, is potentially the result of its destruction box sequence which does not match cyclins B1 and B2.[11][6]

Cyclin B3 seems to maintain this key function in oogenesis in other organisms like Drosophila, where Cyclin B3 acts directly on APC/C, and Caenorhabditis elegans.[18][19][20] Interestingly, injection of frog (Xenopus laevis), zebrafish (Danio rerio), or fly (Drosophila) cyclin B3 mRNA rescued Ccnb3-/- mutant fertility in mice, suggesting that cyclin B3 is highly conserved amongst all animals.[9]

Spermatogenesis

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As its initial mammalian characterization found cyclin B3 is primarily expressed in human testis and implicated in meiosis. Its role in spermatogenesis has been studied in mouse models. Cyclin B3 mRNA is observed beginning in prophase I, and continues to accumulate in leptotene and zygotene stages, decreasing as sperm cells enter the pachytene stage.[8] When cyclin B3 expression is artificially extended until the end of meiosis, spermatogenesis is negatively affected. This extended expression leads to decrease in sperm counts, cells in seminiferous tubules with abnormal morphology and increased instances of apoptosis, and resulted in no functional gametes.[21]

Interestingly, male mice and flies with null or severe loss of function mutations of cyclin B3 (Ccbn3-/Y) retain their fertility and exhibit normal spermatogenesis which shows that cyclin B3 is not necessary for spermatogenesis and has some redundant functionality in males.[22][18]

Cancer

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Despite its primary role in meiosis, cyclin B3 has been implicated in cancer, first described in bone sarcomas as a fusion of BCOR and CCNB3. Tumors with this mutation are relatively rare but more prevalent in adolescents and young adults as well and significantly more common in men than women. No reasons for this demographic breakdown have been proposed.[23][24]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000147082 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051592 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "CCNB3 cyclin B3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-16.
  6. ^ a b c d Gallant P, Nigg EA (February 1994). "Identification of a novel vertebrate cyclin: cyclin B3 shares properties with both A- and B-type cyclins". The EMBO Journal. 13 (3): 595–605. doi:10.1002/j.1460-2075.1994.tb06297.x. PMC 394849. PMID 8313904.
  7. ^ Gunbin KV, Suslov VV, Turnaev II, Afonnikov DA, Kolchanov NA (July 2011). "Molecular evolution of cyclin proteins in animals and fungi". BMC Evolutionary Biology. 11 (1): 224. Bibcode:2011BMCEE..11..224G. doi:10.1186/1471-2148-11-224. PMC 3162929. PMID 21798004.
  8. ^ a b c d e f g Nguyen TB, Manova K, Capodieci P, Lindon C, Bottega S, Wang XY, et al. (November 2002). "Characterization and expression of mammalian cyclin b3, a prepachytene meiotic cyclin". The Journal of Biological Chemistry. 277 (44): 41960–41969. doi:10.1074/jbc.M203951200. PMID 12185076.
  9. ^ a b c Karasu ME, Bouftas N, Keeney S, Wassmann K (April 2019). "Cyclin B3 promotes anaphase I onset in oocyte meiosis". The Journal of Cell Biology. 218 (4): 1265–1281. doi:10.1083/jcb.201808091. PMC 6446836. PMID 30723090.
  10. ^ a b c Lozano JC, Perret E, Schatt P, Arnould C, Peaucellier G, Picard A (February 2002). "Molecular cloning, gene localization, and structure of human cyclin B3". Biochemical and Biophysical Research Communications. 291 (2): 406–413. doi:10.1006/bbrc.2002.6458. PMID 11846420.
  11. ^ a b Kim HM, Kang MK, Seong SY, Jo JH, Kim MJ, Shin EK, et al. (September 2023). "Meiotic Cell Cycle Progression in Mouse Oocytes: Role of Cyclins". International Journal of Molecular Sciences. 24 (17): 13659. doi:10.3390/ijms241713659. PMC 10487953. PMID 37686466.
  12. ^ Tschöp K, Müller GA, Grosche J, Engeland K (April 2006). "Human cyclin B3. mRNA expression during the cell cycle and identification of three novel nonclassical nuclear localization signals". The FEBS Journal. 273 (8): 1681–1695. doi:10.1111/j.1742-4658.2006.05184.x. PMID 16623705.
  13. ^ van der Voet M, Lorson MA, Srinivasan DG, Bennett KL, van den Heuvel S (December 2009). "C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation". Cell Cycle. 8 (24): 4091–4102. doi:10.4161/cc.8.24.10171. PMC 3614003. PMID 19829076.
  14. ^ Deyter GM, Furuta T, Kurasawa Y, Schumacher JM (November 2010). "Caenorhabditis elegans cyclin B3 is required for multiple mitotic processes including alleviation of a spindle checkpoint-dependent block in anaphase chromosome segregation". PLoS Genetics. 6 (11): e1001218. doi:10.1371/journal.pgen.1001218. PMC 2991249. PMID 21124864.
  15. ^ Lara-Gonzalez P, Variyar S, Budrewicz J, Schlientz A, Varshney N, Bellaart A, et al. (August 2023). "Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses". bioRxiv: 2023.08.11.553011. doi:10.1101/2023.08.11.553011. PMC 10441424. PMID 37609212.
  16. ^ Li Y, Wang L, Zhang L, He Z, Feng G, Sun H, et al. (May 2019). "Cyclin B3 is required for metaphase to anaphase transition in oocyte meiosis I". The Journal of Cell Biology. 218 (5): 1553–1563. doi:10.1083/jcb.201808088. PMC 6504906. PMID 30770433.
  17. ^ Bouftas N, Schneider L, Halder M, Demmig R, Baack M, Cladière D, et al. (October 2022). "Cyclin B3 implements timely vertebrate oocyte arrest for fertilization". Developmental Cell. 57 (19): 2305–2320.e6. doi:10.1016/j.devcel.2022.09.005. PMID 36182686.
  18. ^ a b Jacobs HW, Knoblich JA, Lehner CF (December 1998). "Drosophila Cyclin B3 is required for female fertility and is dispensable for mitosis like Cyclin B". Genes & Development. 12 (23): 3741–3751. doi:10.1101/gad.12.23.3741. PMC 317254. PMID 9851980.
  19. ^ Garrido D, Bourouh M, Bonneil É, Thibault P, Swan A, Archambault V (November 2020). "Cyclin B3 activates the Anaphase-Promoting Complex/Cyclosome in meiosis and mitosis". PLoS Genetics. 16 (11): e1009184. doi:10.1371/journal.pgen.1009184. PMC 7660922. PMID 33137813.
  20. ^ Tarailo-Graovac M, Chen N (August 2012). "Proper cyclin B3 dosage is important for precision of metaphase-to-anaphase onset timing in Caenorhabditis elegans". G3. 2 (8): 865–871. doi:10.1534/g3.112.002782. PMC 3411242. PMID 22908035.
  21. ^ Refik-Rogers J, Manova K, Koff A (September 2006). "Misexpression of cyclin B3 leads to aberrant spermatogenesis". Cell Cycle. 5 (17): 1966–1973. doi:10.4161/cc.5.17.3137. PMID 16929180.
  22. ^ Karasu ME, Keeney S (September 2019). "Cyclin B3 is dispensable for mouse spermatogenesis". Chromosoma. 128 (3): 473–487. doi:10.1007/s00412-019-00725-5. PMC 6824995. PMID 31446450.
  23. ^ Krskova L, Kabickova E, Drahokoupilova E, Kopeckova K, Plank L, Vitkova P, et al. (2018). "An undifferentiated sarcoma with BCOR-CCNB3 fusion transcript - pathological and clinical retrospective study". Neoplasma. 65 (4): 630–636. doi:10.4149/neo_2018_171107N716. PMID 30064235.
  24. ^ Pierron G, Tirode F, Lucchesi C, Reynaud S, Ballet S, Cohen-Gogo S, et al. (March 2012). "A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion". Nature Genetics. 44 (4): 461–466. doi:10.1038/ng.1107. PMID 22387997.
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