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Draft:Cyclin B3

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G2/mitotic-specific cyclin-B3 is a protein encoded by the CCNB3 gene located on the X chromosome in humans.[1] 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.[2][3][4][5] However, human cyclin B3 is considerably larger than all other previously characterized invertebrate or vertebrate cyclin B3s.[6] Unlike cyclin B1 and cyclin B2, it is solely expressed in germ cells in mammals, with a significant role in meiosis and gamete formation.[7]

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: rather than containing a leucine it has a phenylalanine. The nuclear localization sequence (NLS) of chicken cyclin B3 appears to be in the 26 C-terminal residues, consistent with A type cyclins.[2]

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.[4][6][8]

Expression

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Cyclin B3 is nearly entirely localized to the nucleus and cycles similarly to other B cyclins in somatic cells.[2][4] In humans it is primarily expressed in germ cells in the testis, somewhat contradictory to its observed function in oocyte meiosis in other organisms.[4][6]

Function

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When it was initially characterized, human cyclin B3 was found to associate with CDK2 in HeLa cells but it did not significantly spur histone H1 kinase activity as is common with other cyclin-CDK complexes. However, further research has not shown that cyclin B3 associates with CDK2 but rather CDK1 (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.[4]

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.[9] Cyclin B3 is especially important in early C. elegans embryos where it again governs chromatid separation as well as kinetochore and microtubule assembly.[10] It additionally appears to drive rapid mitosis in early C. elegans embryos, roughly three times faster than mitosis in adult worms.[11]

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.[4] More recent research[when?] has shown that 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.[5][12]

More recent research[when?] has indicated that cyclin B3-CDK1 complexes phosphorylate Emi2, an APC/C inhibitor, which flags it for degradation and maintains APC/C activity. Importantly, cyclin B3 is not present during meiosis II, which allows for arrest in metaphase II.[13] 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.[7][2]

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.[14][15][16] 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.[5]

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 was observed beginning in prophase I, continuing to accumulate in leptotene and zygotene stages, and decreasing as sperm cells entered the pachytene stage.[4] When cyclin B3 expression was artificially extended until the end of meiosis, spermatogenesis was negatively affected. This extended expression led to decrease in sperm counts, cells in seminiferous tubules with abnormal morphology and increased instances of apoptosis, and resulted in no functional gametes.[17]

Interestingly, male mice and flies with null or severe loss of function mutations of of cyclin B3 (Ccbn3-/Y) retain their fertility and exhibit normal spermatogenesis which shows that cyclin B3 is not necessary and has some redundant functionality in males.[18][14]

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 in undifferentiated sarcomas. 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.[19][20]

References

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  1. ^ "CCNB3 cyclin B3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-16.
  2. ^ a b c d Gallant, P.; Nigg, E. A. (1994-02-01). "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. ISSN 0261-4189. PMC 394849. PMID 8313904.
  3. ^ Gunbin, Konstantin V.; Suslov, Valentin V.; Turnaev, Igor I.; Afonnikov, Dmitry A.; Kolchanov, Nikolay A. (2011-07-28). "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. ISSN 1471-2148. PMC 3162929. PMID 21798004.
  4. ^ a b c d e f g Nguyen, Thomas B.; Manova, Katia; Capodieci, Paola; Lindon, Catherine; Bottega, Steve; Wang, Xiang-Yuan; Refik-Rogers, Jale; Pines, Jonathon; Wolgemuth, Debra J.; Koff, Andrew (2002-11-01). "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. ISSN 0021-9258. PMID 12185076.
  5. ^ a b c Karasu, Mehmet E.; Bouftas, Nora; Keeney, Scott; Wassmann, Katja (2019-04-01). "Cyclin B3 promotes anaphase I onset in oocyte meiosis". The Journal of Cell Biology. 218 (4): 1265–1281. doi:10.1083/jcb.201808091. ISSN 1540-8140. PMC 6446836. PMID 30723090.
  6. ^ a b c Lozano, Jean-Claude; Perret, Eric; Schatt, Philippe; Arnould, Cécile; Peaucellier, Gérard; Picard, André (2002-02-22). "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. ISSN 0006-291X. PMID 11846420.
  7. ^ a b Kim, Hye Min; Kang, Min Kook; Seong, Se Yoon; Jo, Jun Hyeon; Kim, Min Ju; Shin, Eun Kyeong; Lee, Chang Geun; Han, Seung Jin (2023-09-04). "Meiotic Cell Cycle Progression in Mouse Oocytes: Role of Cyclins". International Journal of Molecular Sciences. 24 (17): 13659. doi:10.3390/ijms241713659. ISSN 1422-0067. PMC 10487953. PMID 37686466.
  8. ^ Tschöp, Katrin; Müller, Gerd A.; Grosche, Jens; Engeland, Kurt (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. ISSN 1742-464X. PMID 16623705.
  9. ^ van der Voet, Monique; Lorson, Monique A.; Srinivasan, Dayalan G.; Bennett, Karen L.; van den Heuvel, Sander (2009-12-15). "C. elegans mitotic cyclins have distinct as well as overlapping functions in chromosome segregation". Cell Cycle (Georgetown, Tex.). 8 (24): 4091–4102. doi:10.4161/cc.8.24.10171. ISSN 1551-4005. PMC 3614003. PMID 19829076.
  10. ^ Deyter, Gary M. R.; Furuta, Tokiko; Kurasawa, Yasuhiro; Schumacher, Jill M. (2010-11-24). "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. ISSN 1553-7404. PMC 2991249. PMID 21124864.
  11. ^ Lara-Gonzalez, Pablo; Variyar, Smriti; Budrewicz, Jacqueline; Schlientz, Aleesa; Varshney, Neha; Bellaart, Andrew; Moghareh, Shabnam; Nguyen, Anh Cao Ngoc; Oegema, Karen; Desai, Arshad (2023-08-11). "Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses". BioRxiv: The Preprint Server for Biology: 2023.08.11.553011. doi:10.1101/2023.08.11.553011. ISSN 2692-8205. PMC 10441424. PMID 37609212.
  12. ^ Li, Yufei; Wang, Leyun; Zhang, Linlin; He, Zhengquan; Feng, Guihai; Sun, Hao; Wang, Jiaqiang; Li, Zhikun; Liu, Chao; Han, Jiabao; Mao, Junjie; Li, Pengcheng; Yuan, Xuewei; Jiang, Liyuan; Zhang, Ying (2019-05-06). "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. ISSN 1540-8140. PMC 6504906. PMID 30770433.
  13. ^ Bouftas, Nora; Schneider, Lena; Halder, Marc; Demmig, Rebecca; Baack, Martina; Cladière, Damien; Walter, Melanie; Al Abdallah, Hiba; Kleinhempel, Camilla; Messaritaki, Ria; Müller, Janina; Passarelli, Francesca; Wehrle, Patrick; Heim, Andreas; Wassmann, Katja (2022-10-10). "Cyclin B3 implements timely vertebrate oocyte arrest for fertilization". Developmental Cell. 57 (19): 2305–2320.e6. doi:10.1016/j.devcel.2022.09.005. ISSN 1878-1551. PMID 36182686.
  14. ^ a b Jacobs, H. W.; Knoblich, J. A.; Lehner, C. F. (1998-12-01). "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. ISSN 0890-9369. PMC 317254. PMID 9851980.
  15. ^ Garrido, Damien; Bourouh, Mohammed; Bonneil, Éric; Thibault, Pierre; Swan, Andrew; Archambault, Vincent (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. ISSN 1553-7404. PMC 7660922. PMID 33137813.
  16. ^ Tarailo-Graovac, Maja; Chen, Nansheng (August 2012). "Proper cyclin B3 dosage is important for precision of metaphase-to-anaphase onset timing in Caenorhabditis elegans". G3 (Bethesda, Md.). 2 (8): 865–871. doi:10.1534/g3.112.002782. ISSN 2160-1836. PMC 3411242. PMID 22908035.
  17. ^ Refik-Rogers, Jale; Manova, Katia; Koff, Andrew (2006-08-11). "Misexpression of cyclin B3 leads to aberrant spermatogenesis". Cell Cycle (Georgetown, Tex.). 5 (17): 1966–1973. doi:10.4161/cc.5.17.3137. ISSN 1551-4005. PMID 16929180.
  18. ^ Karasu, Mehmet E.; Keeney, Scott (2019-08-24). "Cyclin B3 is dispensable for mouse spermatogenesis". Chromosoma. 128 (3): 473–487. doi:10.1007/s00412-019-00725-5. ISSN 1432-0886. PMC 6824995. PMID 31446450.
  19. ^ Krskova, L.; Kabickova, E.; Drahokoupilova, E.; Kopeckova, K.; Plank, L.; Vitkova, P.; Mrhalova, M.; Zamecnik, J.; Kodet, R. (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. ISSN 0028-2685. PMID 30064235.
  20. ^ Pierron, Gaëlle; Tirode, Franck; Lucchesi, Carlo; Reynaud, Stéphanie; Ballet, Stelly; Cohen-Gogo, Sarah; Perrin, Virginie; Coindre, Jean-Michel; Delattre, Olivier (2012-03-04). "A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion". Nature Genetics. 44 (4): 461–466. doi:10.1038/ng.1107. ISSN 1546-1718. PMID 22387997.
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