Cyclin A2 Explained

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene.^[1] It is one of the two types of cyclin A: cyclin A1 is expressed during meiosis and embryogenesis while cyclin A2 is expressed in the mitotic division of somatic cells.^[2]

Function

Cyclin A2 belongs to the cyclin family, whose members regulate cell cycle progression by interacting with CDK kinases. Cyclin A2 is unique in that it can activate two different CDK kinases; it binds CDK2 during S phase, and CDK1 during the transition from G2 to M phase.^[3]

Cyclin A2 is synthesized at the onset of S phase and localizes to the nucleus, where the cyclin A2-CDK2 complex is implicated in the initiation and progression of DNA synthesis. Phosphorylation of CDC6 and MCM4 by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle.^[2]

Cyclin A2 is involved in the G2/M transition but it cannot independently form a maturation promoting factor (MPF).^[4] Recent studies have shown that the cyclin A2-CDK1 complex triggers cyclin B1-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope.^[5]

Regulation

The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle.^[6] Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2.^[6]

Cyclin A2 transcription is mostly regulated by the transcription factor E2F and begins in G1, after the R point.^[6] Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated retinoblastoma protein (pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription.^{[7] [8]} The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription.^[6] E2F promotes cyclin A2 transcription by de-repressing the promoter.^{[6] [7]}

Interactions

Cyclin A2 has been shown to interact with:

• CDC6,^{[9] [10]}
• E2F1,
• FEN1,^[11]
• ITGB3BP,^[12]
• RBL1,^{[13] [14]} and
• SKP2.^{[15] [16]}

DNA Repair

Cyclin A2 regulates homologous recombinational DNA repair in human breast cancer cells^[17] Loss of cyclin A2 causes high rates of double-strand breaks in DNA. The increase in double-strand breaks is a consequence of defective homologous recombinational repair of the breaks resulting from reduced MRE11 and RAD51 DNA repair proteins.^[17] Cyclin A2 mediates the abundance of MRE11 nuclease by binding to Mre11 mRNA. Cyclin A2 mediates the abundance of RAD51 protein by inhibiting proteasome degradation of this protein.

During mouse development and aging, cyclin A2 promotes DNA repair, particularly double-strand break repair, in the brain.^[18] Also in mice, cyclin A2 was found to be an RNA binding protein that controls the translation of Mre11 mRNA.^[19]

Clinical significance

Cyclin A2 (Ccna2) is a key protein involved in the direction of mammalian cardiac myocytes to grow and divide, and has been shown to induce cardiac repair following myocardial infarction. Normally, Ccna2 is silenced postnatally in mammalian cardiac myocytes. Because of this gene silencing, adult heart muscle cells cannot divide readily to repair and regenerate after a heart attack.

Ccna2 has been found to induce cardiac repair in small-animal models following myocardial infarction.^[20] Preclinical trials involving injections of adenovirus which contained the Ccna2 gene into infarcted porcine (pig) hearts has shown to be protective of MI in pig hearts.^[20] Ccna2 mediated cardiac repair showed both a decrease in fibrosis in the peri-infarct tissue and a greater number of cardiomyocytes at the sites of injection.^[20] Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function.^{[20] [21] [22]}

Cancer

Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others.^{[2] [23] [24] [25] [26]} While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis, it is indicative of prognostic values such as predictions of survival or relapse.^[2]

Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase and anaphase.^[27] It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins or tumor suppressors like p53.^[28]

See also

• Cyclin A

Further reading

• Bailly E, Pines J, Hunter T, Bornens M . Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome . J. Cell Sci. . 101 . 3 . 529–545 . 1992 . 10.1242/jcs.101.3.529 . 1387877 .
• Faha B, Ewen ME, Tsai LH, Livingston DM, Harlow E . Interaction between human cyclin A and adenovirus E1A-associated p107 protein . Science . 255 . 5040 . 87–90 . 1992 . 1532458 . 10.1126/science.1532458 . 1992Sci...255...87F .
• Bandara LR, Adamczewski JP, Hunt T, La Thangue NB . Cyclin A and the retinoblastoma gene product complex with a common transcription factor . Nature . 352 . 6332 . 249–251 . 1991 . 1830372 . 10.1038/352249a0 . 1991Natur.352..249B . 1019851 .
• Blanquet V, Wang JA, Chenivesse X, Henglein B, Garreau F, Bréchot C, Turleau C . Assignment of a human cyclin A gene to 4q26-q27 . Genomics . 8 . 3 . 595–597 . 1990 . 1962755 . 10.1016/0888-7543(90)90052-V .
• Wang J, Chenivesse X, Henglein B, Bréchot C . Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma . Nature . 343 . 6258 . 555–557 . 1990 . 1967822 . 10.1038/343555a0 . 1990Natur.343..555W . 4269638 .
• Jeffrey PD, Russo AA, Polyak K, Gibbs E, Hurwitz J, Massagué J, Pavletich NP . Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex . Nature . 376 . 6538 . 313–320 . 1995 . 7630397 . 10.1038/376313a0 . 1995Natur.376..313J . 4361179 .
• Castro A, Jaumot M, Vergés M, Agell N, Bachs O . Microsomal localization of cyclin A and cdk2 in proliferating rat liver cells . Biochem. Biophys. Res. Commun. . 201 . 3 . 1072–1078 . 1994 . 8024548 . 10.1006/bbrc.1994.1814 .
• Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K . Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 . J. Virol. . 67 . 12 . 7641–7647 . 1993 . 8230483 . 238233 . 10.1128/JVI.67.12.7641-7647.1993.
• Li Y, Graham C, Lacy S, Duncan AM, Whyte P . The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E . Genes Dev. . 7 . 12A . 2366–2377 . 1993 . 8253383 . 10.1101/gad.7.12a.2366 . free .
• Lees EM, Harlow E . Sequences within the conserved cyclin box of human cyclin A are sufficient for binding to and activation of cdc2 kinase . Mol. Cell. Biol. . 13 . 2 . 1194–1201 . 1993 . 8423786 . 359004 . 10.1128/MCB.13.2.1194.
• Sebastian B, Kakizuka A, Hunter T . Cdc25M2 activation of cyclin-dependent kinases by dephosphorylation of threonine-14 and tyrosine-15 . Proc. Natl. Acad. Sci. U.S.A. . 90 . 8 . 3521–3524 . 1993 . 8475101 . 46332 . 10.1073/pnas.90.8.3521 . 1993PNAS...90.3521S . free .
• Carbonaro-Hall D, Williams R, Wu L, Warburton D, Zeichner-David M, MacDougall M, Tolo V, Hall F . G1 expression and multistage dynamics of cyclin A in human osteosarcoma cells . Oncogene . 8 . 6 . 1649–1659 . 1993 . 8502485 .
• Meikrantz W, Schlegel R . Suppression of apoptosis by dominant negative mutants of cyclin-dependent protein kinases . J. Biol. Chem. . 271 . 17 . 10205–10209 . 1996 . 8626584 . 10.1074/jbc.271.17.10205 . free .
• Poon RY, Jiang W, Toyoshima H, Hunter T . Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage . J. Biol. Chem. . 271 . 22 . 13283–13291 . 1996 . 8662825 . 10.1074/jbc.271.22.13283 . free .
• Russo AA, Jeffrey PD, Patten AK, Massagué J, Pavletich NP . Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex . Nature . 382 . 6589 . 325–331 . 1996 . 8684460 . 10.1038/382325a0 . 1996Natur.382..325R . 4284942 .
• Russo AA, Jeffrey PD, Pavletich NP . Structural basis of cyclin-dependent kinase activation by phosphorylation . Nat. Struct. Biol. . 3 . 8 . 696–700 . 1996 . 8756328 . 10.1038/nsb0896-696 . 383015 .

Notes and References

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2. Yam CH, Fung TK, Poon RY . Cyclin A in cell cycle control and cancer . Cell. Mol. Life Sci. . 59 . 8 . 1317–1326 . Aug 2002 . 12363035 . 10.1007/s00018-002-8510-y . 97398 .
3. Pagano M, Pepperkok R, Verde F, Ansorge W, Draetta G . Cyclin A is required at two points in the human cell cycle . EMBO J. . 11 . 3 . 961–971 . March 1992 . 1312467 . 556537 . 10.1002/j.1460-2075.1992.tb05135.x.
4. Fung TK, Ma HT, Poon RY . Specialized roles of the two mitotic cyclins in somatic cells: cyclin A as an activator of M phase-promoting factor . Mol. Biol. Cell . 18 . 5 . 1861–1873 . Mar 2007 . 17344473 . 1855023 . 10.1091/mbc.E06-12-1092 .
5. Gong D, Ferrell JE . The roles of cyclin A2, B1, and B2 in early and late mitotic events . Mol. Biol. Cell . 21 . 18 . 3149–3161 . Sep 2010 . 20660152 . 2938381 . 10.1091/mbc.E10-05-0393 .
6. Henglein B, Chenivesse X, Wang J, Eick D, Bréchot C . Structure and cell cycle-regulated transcription of the human cyclin A gene . Proc. Natl. Acad. Sci. U.S.A. . 91 . 12 . 5490–5494 . Jun 1994 . 8202514 . 44021 . 10.1073/pnas.91.12.5490 . 1994PNAS...91.5490H . free .
7. Woo RA, Poon RY . Cyclin-dependent kinases and S phase control in mammalian cells . Cell Cycle . 2 . 4 . 316–324 . Jul–Aug 2003 . 12851482 . 10.4161/cc.2.4.468 . free .
8. Xu M, Sheppard KA, Peng CY, Yee AS, Piwnica-Worms H . Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding activity of E2F-1/DP-1 by phosphorylation . Mol. Cell. Biol. . 14 . 12 . 8420–8431 . 1994 . 7969176 . 359381 . 10.1128/MCB.14.12.8420.
9. Petersen BO, Lukas J, Sørensen CS, Bartek J, Helin K . Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its subcellular localization . EMBO J. . 18 . 2 . 396–410 . January 1999 . 9889196 . 1171134 . 10.1093/emboj/18.2.396 .
10. Saha P, Chen J, Thome KC, Lawlis SJ, Hou ZH, Hendricks M, Parvin JD, Dutta A . Human CDC6/Cdc18 associates with Orc1 and cyclin-cdk and is selectively eliminated from the nucleus at the onset of S phase . Mol. Cell. Biol. . 18 . 5 . 2758–2767 . May 1998 . 9566895 . 110655 . 10.1128/mcb.18.5.2758.
11. Henneke G, Koundrioukoff S, Hübscher U . Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation . Oncogene . 22 . 28 . 4301–4313 . July 2003 . 12853968 . 10.1038/sj.onc.1206606 . 5787920 .
12. Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Yamada M, Hatakeyama M . beta3-endonexin as a novel inhibitor of cyclin A-associated kinase . Biochem. Biophys. Res. Commun. . 267 . 3 . 947–952 . January 2000 . 10673397 . 10.1006/bbrc.1999.2007 .
13. Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K . Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1 . J. Virol. . 67 . 12 . 7641–7647 . December 1993 . 8230483 . 238233 . 10.1128/JVI.67.12.7641-7647.1993.
14. Joaquin M, Bessa M, Saville MK, Watson RJ . B-Myb overcomes a p107-mediated cell proliferation block by interacting with an N-terminal domain of p107 . Oncogene . 21 . 52 . 7923–7932 . November 2002 . 12439743 . 10.1038/sj.onc.1206001 . 21761703 .
15. Rosner M, Hengstschläger M . Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2 . J. Biol. Chem. . 279 . 47 . 48707–48715 . November 2004 . 15355997 . 10.1074/jbc.M405528200 . free .
16. Marti A, Wirbelauer C, Scheffner M, Krek W . Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation . Nat. Cell Biol. . 1 . 1 . 14–19 . May 1999 . 10559858 . 10.1038/8984 . 8884226 .
17. Gu WW, Lin J, Hong XY . Cyclin A2 regulates homologous recombination DNA repair and sensitivity to DNA damaging agents and poly(ADP-ribose) polymerase (PARP) inhibitors in human breast cancer cells . Oncotarget . 8 . 53 . 90842–90851 . October 2017 . 29207607 . 5710888 . 10.18632/oncotarget.20412 .
18. Gygli PE, Chang JC, Gokozan HN, Catacutan FP, Schmidt TA, Kaya B, Goksel M, Baig FS, Chen S, Griveau A, Michowski W, Wong M, Palanichamy K, Sicinski P, Nelson RJ, Czeisler C, Otero JJ . 6 . Cyclin A2 promotes DNA repair in the brain during both development and aging . Aging . 8 . 7 . 1540–1570 . July 2016 . 27425845 . 4993346 . 10.18632/aging.100990 .
19. Kanakkanthara A, Jeganathan KB, Limzerwala JF, Baker DJ, Hamada M, Nam HJ, van Deursen WH, Hamada N, Naylor RM, Becker NA, Davies BA, van Ree JH, Mer G, Shapiro VS, Maher LJ, Katzmann DJ, van Deursen JM . 6 . Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation . Science . 353 . 6307 . 1549–1552 . September 2016 . 27708105 . 5109925 . 10.1126/science.aaf7463 . 2016Sci...353.1549K .
20. Shapiro SD, Ranjan AK, Kawase Y, Cheng RK, Kara RJ, Bhattacharya R, Guzman-Martinez G, Sanz J, Garcia MJ, Chaudhry HW . Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes . Sci Transl Med . 6 . 224 . 224ra27 . 2014 . 24553388 . 10.1126/scitranslmed.3007668 . 20386712 .
21. Woo YJ, Panlilio CM, Cheng RK, Liao GP, Suarez EE, Atluri P, Chaudhry HW . Myocardial regeneration therapy for ischemic cardiomyopathy with cyclin A2 . J. Thorac. Cardiovasc. Surg. . 133 . 4 . 927–933 . 2007 . 17382628 . 10.1016/j.jtcvs.2006.07.057 . free .
22. Laflamme MA, Murry CE . Heart regeneration . Nature . 473 . 7347 . 326–335 . 2011 . 21593865 . 4091722 . 10.1038/nature10147 . 2011Natur.473..326L .
23. Bukholm IR, Bukholm G, Nesland JM . Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas . Int. J. Cancer . 93 . 2 . 283–287 . Jul 2001 . 11410878 . 10.1002/ijc.1311 . 10543682 .
24. Kanai M, Shiozawa T, Xin L, Nikaido T, Fujii S . Immunohistochemical detection of sex steroid receptors, cyclins, and cyclin-dependent kinases in the normal and neoplastic squamous epithelia of the uterine cervix . Cancer . 82 . 9 . 1709–1719 . May 1998 . 9576293 . 10.1002/(sici)1097-0142(19980501)82:9<1709::aid-cncr18>3.0.co;2-8 . 46236286 . free .
25. Ohashi R, Gao C, Miyazaki M, Hamazaki K, Tsuji T, Inoue Y, Uemura T, Hirai R, Shimizu N, Namba M . Enhanced expression of cyclin E and cyclin A in human hepatocellular carcinomas . Anticancer Res. . 21 . 1B . 657–662 . Jan–Feb 2001 . 11299822 .
26. Volm M, Koomägi R, Mattern J, Stammler G . Cyclin A is associated with an unfavourable outcome in patients with non-small-cell lung carcinomas . Br. J. Cancer . 75 . 12 . 1774–1778 . 1997 . 9192980 . 2223613 . 10.1038/bjc.1997.302 .
27. den Elzen N, Pines J . Cyclin A is destroyed in prometaphase and can delay chromosome alignment and anaphase . J. Cell Biol. . 153 . 1 . 121–136 . Apr 2001 . 11285279 . 2185531 . 10.1083/jcb.153.1.121 .
28. Wang Y, Prives C . Increased and altered DNA binding of human p53 by S and G2/M but not G1 cyclin-dependent kinases . Nature . 376 . 6535 . 88–91 . Jul 1995 . 7596441 . 10.1038/376088a0 . 1995Natur.376...88W . 4240439 .