* 123835

CYCLIN A2; CCNA2


Alternative titles; symbols

CYCLIN A; CCNA


HGNC Approved Gene Symbol: CCNA2

Cytogenetic location: 4q27     Genomic coordinates (GRCh38): 4:121,816,444-121,823,883 (from NCBI)


TEXT

Description

Cyclin A2 is an essential component of all embryonic and somatic cell cycles in mammals (Murphy et al., 1997).


Cloning and Expression

Wang et al. (1990) cloned a single hepatitis B virus integration site in a human hepatocellular carcinoma at an early stage of development, and also cloned its germline counterpart. The normal locus was found to be transcribed into 2 polyadenylated mRNA species of 1.8 and 2.7 kb. Wang et al. (1990) isolated a cDNA clone from a normal adult human liver that had an open reading frame with a coding capacity for a protein of 432 amino acids and relative molecular mass of 48,536. Strong homologies in amino acid sequence identified the protein as a human cyclin A. The HBV integration was found to have occurred within an intron.


Gene Function

Wang et al. (1990) suggested that disruption of the cyclin A gene by viral insertion was responsible for tumorigenesis. Cyclins are highly conserved proteins associated with proliferating cells. They show a steady accumulation throughout interphase until the G2/M transition, followed by rapid disappearance at the onset of anaphase. They are highly conserved in evolution, having been identified in yeast, clam, starfish, sea urchin, and Drosophila. Two groups of cyclins, A and B, are distinguished on the basis of their sequence and pattern of accumulation during the cell cycle. Both cyclins will complex with and activate the serine-threonine kinase p34(cdc2) during the G2/M phase transition; see 116940. Cyclins are also referred to as proliferating cell nuclear antigens (176740). Nonrandom integration of HBV in hepatocellular carcinoma has been related to chromosome 11 (114550) and to chromosome 4, where the cyclin A gene maps. Furthermore, interruption of the coding region of the gene for retinoic acid receptor beta (RARB; 180220) by viral DNA has been reported (summary by Wang et al., 1990).

Girard et al. (1991) showed that cyclin A protein is synthesized and localized into the nucleus at the onset of S phase in nontransformed mammalian fibroblasts. Inhibition of cyclin A synthesis or activity through microinjection of plasmids encoding antisense cyclin A cDNA or affinity-purified anti-cyclin A antibodies during G1 phase abolished the nuclear staining for cyclin A and inhibited DNA synthesis. No similar effect was observed with injection of other antisense vectors, including antisense cyclin B. Girard et al. (1991) suggested that cyclin A plays a major role in the control of DNA replication. Henglein et al. (1994) cloned and sequenced the human CCNA gene and cDNAs representing its mRNAs and characterized its promoter. Using synchronized cultures of NIH 3T3 cells stably transfected with cyclin A promoter/luciferase constructs, they showed that the promoter is repressed during the G1 phase of the cell cycle and is activated at S-phase entry. Cell cycle regulation of the CCNA promoter is mediated by sequences extending from -79 to +100 relative to the predominant transcription start site. The presence of a functional retinoblastoma protein is not required.

Hunter and Pines (1991) gave a review of the role of cyclins in cancer.

Cyclin A2 is first detected during S phase, then shuttles dynamically between the cytoplasm and nucleus, and is finally degraded during prometaphase. Using RNA interference and time-lapse fluorescence microscopy with synchronized HeLa cells, Gong and Ferrell (2010) found that cyclin A2 was required for activation and nuclear accumulation of cyclin B1 (CCNB1; 123836)-CDK1 (116940), as well as timely breakdown of the nuclear envelope, histone H3 phosphorylation, and chromatin condensation. Expression of constitutively nuclear cyclin B1 abrogated many of these effects. In contrast with knockdown of cyclin A2, knockdown of cyclin B1, or, more potently, of both cyclins B1 and B2 (CCNB2; 602755), had more dramatic effects on later mitotic events. Gong and Ferrell (2010) hypothesized that cyclin A2 helps initiate mitosis, in part by activating cyclin B1-CDK1 activation and nuclear translocation.

Kabeche and Compton (2013) found that kinetochore-microtubule (k-MT) attachments in prometaphase cells are considerably less stable than in metaphase cells, and that the switch to more stable k-MT attachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase. Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. By contrast, k-MTs are prematurely stabilized in cyclin A-deficient cells. Consequently, cells lacking cyclin A display higher rates of chromosome missegregation. Thus, the stability of k-MT attachments increases decisively in a coordinated fashion among all chromosomes as cells transit from prometaphase to metaphase. Cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.

Liu et al. (2014) reported that AKT (164730) activity fluctuates across the cell cycle, mirroring CCNA2 expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase-2 (CDK2; 116953)/CCNA2 or mTORC2 (see 601231), under distinct physiologic conditions, promoted Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of both Ccna2 alleles in the mouse olfactory bulb led to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, Ccna2 deletion-induced cellular apoptosis in mouse embryonic stem cells was partly rescued by S477D/T479E-Akt1, supporting a physiologic role for Ccna2 in governing Akt activation. Liu et al. (2014) concluded that, taken together, the results of their study showed AKT S477/T479 phosphorylation to be an essential layer of the AKT activation mechanism to regulate its physiologic functions, thereby providing a mechanistic link between aberrant cell cycle progression and AKT hyperactivation in cancer.

Kanakkanthara et al. (2016) found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to upregulate the meiotic recombination-11 (MRE11; 600814) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. Kanakkanthara et al. (2016) concluded that their data revealed cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding-dependent role that ensures adequate repair of common replication errors.

The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2/CDK2 and RB1 (614041), leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4 (123829)/CDK6 (603368) promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost.


Mapping

By in situ hybridization, Blanquet et al. (1990) mapped the CCNA gene to 4q26-q27. They pointed to the interest of this finding in connection with the demonstrated loss of heterozygosity for markers on 4q in tumor tissue of patients with liver cancer (Buetow et al., 1989). By genetic mapping using a cyclin A probe, Lock et al. (1992) demonstrated a single Cyca gene on mouse chromosome 3.


Molecular Genetics

For discussion of a possible association between variation in the CCNA2 gene and autosomal recessive intellectual developmental disorder-29 (614333), see 123835.0001.


Animal Model

The mammalian A-type cyclin family consists of 2 members, cyclin A1 (CCNA1; 604036) and cyclin A2 (CCNA2). Cyclin A2 promotes both G1/S and G2/M transitions (Pagano et al., 1992). Murphy et al. (1997) demonstrated that a targeted deletion of the murine Ccna2 gene is embryonically lethal, although homozygous null mutant embryos developed normally until postimplantation, approximately day 5.5 postcoitum. The authors suggested that the embryos survived either because a maternal pool of cyclin A2 protein persists until at least the blastocyst stage, or because cyclin A1 plays an unexpected role during early embryo development. In an erratum, the authors stated that maternal cyclin A2 cannot be considered to persist to the blastocyst stage during early mouse development. Cyclin A1 is expressed in mice exclusively in the germline lineage (Sweeney et al., 1996) and is expressed in humans at highest levels in the testis and certain myeloid leukemia cells (Yang et al., 1997).


ALLELIC VARIANTS ( 1 Selected Example):

.0001 VARIANT OF UNKNOWN SIGNIFICANCE

CCNA2, 1-BP INS
  
RCV000255886

This variant is classified as a variant of unknown significance because its contribution to autosomal recessive intellectual developmental disorder-29 (MRT29; 614333) has not been confirmed.

In affected members of a consanguineous Iranian family (M346) with autosomal recessive intellectual developmental disorder mapped to chromosome 4q by Kuss et al. (2011), Najmabadi et al. (2011) identified homozygosity for a 1-bp deletion (chr4:122,963,253_122,963,254ins1) in the CCNA2 gene. No functional studies were performed.


REFERENCES

  1. Blanquet, V., Wang, J., Chenivesse, X., Henglein, B., Garreau, F., Brechot, C., Turleau, C. Assignment of a human cyclin A gene to 4q26-q27. Genomics 8: 595-597, 1990. [PubMed: 1962755, related citations] [Full Text]

  2. Buetow, K. H., Murray, J. E., Israel, J. L., London, W. T., Smith, M., Kew, M., Blanquet, V., Brechot, C., Redeker, A., Govindarajah, S. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc. Nat. Acad. Sci. 86: 8852-8856, 1989. [PubMed: 2573067, related citations] [Full Text]

  3. Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D. Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal. Nature 619: 363-370, 2023. [PubMed: 37407814, images, related citations] [Full Text]

  4. Girard, F., Strausfeld, U., Fernandez, A., Lamb, N. J. C. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: 1169-1179, 1991. [PubMed: 1836977, related citations] [Full Text]

  5. Gong, D., Ferrell, J. E., Jr. The roles of cyclin A2, B1, and B2 in early and late mitotic events. Molec. Biol. Cell 21: 3149-3161, 2010. [PubMed: 20660152, images, related citations] [Full Text]

  6. Henglein, B., Chenivesse, X., Wang, J., Eick, D., Brechot, C. Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc. Nat. Acad. Sci. 91: 5490-5494, 1994. [PubMed: 8202514, related citations] [Full Text]

  7. Hunter, T., Pines, J. Cyclins and cancer. Cell 66: 1071-1074, 1991. [PubMed: 1833062, related citations] [Full Text]

  8. Kabeche, L., Compton, D. A. Cyclin A regulates kinetochore microtubules to promote faithful chromosome segregation. Nature 502: 110-113, 2013. [PubMed: 24013174, images, related citations] [Full Text]

  9. Kanakkanthara, A., Jeganathan, K. B., Limzerwala, J. F., Baker, D. J., Hamada, M., Nam, H.-J., van Deursen, W. H., Hamada, N., Naylor, R. M., Becker, N. A., Davies, B. A., van Ree, J. H., Mer, G., Shapiro, V. S., Maher, L. J., III, Katzmann, D. J., van Deursen, J. M. Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science 353: 1549-1552, 2016. [PubMed: 27708105, images, related citations] [Full Text]

  10. Kuss, A. W., Garshasbi, M., Kahrizi, K., Tzschach, A., Behjati, F., Darvish, H., Abbasi-Moheb, L., Puettmann, L., Zecha, A., Weissmann, R., Hu, H., Mohseni, M., and 18 others. Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum. Genet. 129: 141-148, 2011. [PubMed: 21063731, related citations] [Full Text]

  11. Liu, P., Begley, M., Michowski, W., Inuzuka, H., Ginzberg, M., Gao, D., Tsou, P., Gan, W., Papa, A., Kim, B. M., Wan, L., Singh, A., and 13 others. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508: 541-545, 2014. [PubMed: 24670654, images, related citations] [Full Text]

  12. Lock, L. F., Pines, J., Hunter, T., Gilbert, D. J., Gopalan, G., Jenkins, N. A., Copeland, N. G., Donovan, P. J. A single cyclin A gene and multiple cyclin B1-related sequences are dispersed in the mouse genome. Genomics 13: 415-424, 1992. [PubMed: 1535334, related citations] [Full Text]

  13. Murphy, M., Stinnakre, M. G., Senamaud-Beaufort, C., Winston, N. J., Sweeney, C., Kubelka, M., Carrington, M., Brechot, C., Sobczak-Thepot, J. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nature Genet. 15: 83-86, 1997. Note: Erratum: Nature Genet. 23: 481 only, 1999. [PubMed: 8988174, related citations] [Full Text]

  14. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57-63, 2011. [PubMed: 21937992, related citations] [Full Text]

  15. 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: 961-971, 1992. [PubMed: 1312467, related citations] [Full Text]

  16. Sweeney, C., Murphy, M., Kubelka, M., Ravnik. S. E., Hawkins, C. F., Wolgenmuth, D. J., Carrington, M. A distinct cyclin A is expressed in germ cells in the mouse. Development 122: 53-64, 1996. [PubMed: 8565853, related citations] [Full Text]

  17. Wang, J., Chenivesse, X., Henglein, B., Brechot, C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343: 555-557, 1990. [PubMed: 1967822, related citations] [Full Text]

  18. Yang, R., Morosetti, R., Koeffler, H. P. Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines. Cancer Res. 57: 913-920, 1997. [PubMed: 9041194, related citations]


Bao Lige - updated : 02/08/2024
Ada Hamosh - updated : 12/21/2016
Carol A. Bocchini - updated : 10/05/2016
Patricia A. Hartz - updated : 7/22/2014
Ada Hamosh - updated : 5/30/2014
Ada Hamosh - updated : 12/5/2013
Rebekah S. Rasooly - updated : 7/21/1999
Victor A. McKusick - updated : 11/30/1998
Creation Date:
Victor A. McKusick : 2/27/1990
mgross : 02/08/2024
carol : 04/07/2022
alopez : 12/21/2016
carol : 10/10/2016
carol : 10/05/2016
mgross : 10/10/2014
mcolton : 7/22/2014
alopez : 5/30/2014
alopez : 12/5/2013
carol : 12/17/2012
alopez : 2/23/2011
terry : 5/20/2010
terry : 1/22/2001
mgross : 7/21/1999
dkim : 12/2/1998
alopez : 12/1/1998
terry : 11/30/1998
carol : 6/28/1994
jason : 6/22/1994
carol : 3/9/1993
carol : 6/24/1992
supermim : 3/16/1992
carol : 2/17/1992

* 123835

CYCLIN A2; CCNA2


Alternative titles; symbols

CYCLIN A; CCNA


HGNC Approved Gene Symbol: CCNA2

Cytogenetic location: 4q27     Genomic coordinates (GRCh38): 4:121,816,444-121,823,883 (from NCBI)


TEXT

Description

Cyclin A2 is an essential component of all embryonic and somatic cell cycles in mammals (Murphy et al., 1997).


Cloning and Expression

Wang et al. (1990) cloned a single hepatitis B virus integration site in a human hepatocellular carcinoma at an early stage of development, and also cloned its germline counterpart. The normal locus was found to be transcribed into 2 polyadenylated mRNA species of 1.8 and 2.7 kb. Wang et al. (1990) isolated a cDNA clone from a normal adult human liver that had an open reading frame with a coding capacity for a protein of 432 amino acids and relative molecular mass of 48,536. Strong homologies in amino acid sequence identified the protein as a human cyclin A. The HBV integration was found to have occurred within an intron.


Gene Function

Wang et al. (1990) suggested that disruption of the cyclin A gene by viral insertion was responsible for tumorigenesis. Cyclins are highly conserved proteins associated with proliferating cells. They show a steady accumulation throughout interphase until the G2/M transition, followed by rapid disappearance at the onset of anaphase. They are highly conserved in evolution, having been identified in yeast, clam, starfish, sea urchin, and Drosophila. Two groups of cyclins, A and B, are distinguished on the basis of their sequence and pattern of accumulation during the cell cycle. Both cyclins will complex with and activate the serine-threonine kinase p34(cdc2) during the G2/M phase transition; see 116940. Cyclins are also referred to as proliferating cell nuclear antigens (176740). Nonrandom integration of HBV in hepatocellular carcinoma has been related to chromosome 11 (114550) and to chromosome 4, where the cyclin A gene maps. Furthermore, interruption of the coding region of the gene for retinoic acid receptor beta (RARB; 180220) by viral DNA has been reported (summary by Wang et al., 1990).

Girard et al. (1991) showed that cyclin A protein is synthesized and localized into the nucleus at the onset of S phase in nontransformed mammalian fibroblasts. Inhibition of cyclin A synthesis or activity through microinjection of plasmids encoding antisense cyclin A cDNA or affinity-purified anti-cyclin A antibodies during G1 phase abolished the nuclear staining for cyclin A and inhibited DNA synthesis. No similar effect was observed with injection of other antisense vectors, including antisense cyclin B. Girard et al. (1991) suggested that cyclin A plays a major role in the control of DNA replication. Henglein et al. (1994) cloned and sequenced the human CCNA gene and cDNAs representing its mRNAs and characterized its promoter. Using synchronized cultures of NIH 3T3 cells stably transfected with cyclin A promoter/luciferase constructs, they showed that the promoter is repressed during the G1 phase of the cell cycle and is activated at S-phase entry. Cell cycle regulation of the CCNA promoter is mediated by sequences extending from -79 to +100 relative to the predominant transcription start site. The presence of a functional retinoblastoma protein is not required.

Hunter and Pines (1991) gave a review of the role of cyclins in cancer.

Cyclin A2 is first detected during S phase, then shuttles dynamically between the cytoplasm and nucleus, and is finally degraded during prometaphase. Using RNA interference and time-lapse fluorescence microscopy with synchronized HeLa cells, Gong and Ferrell (2010) found that cyclin A2 was required for activation and nuclear accumulation of cyclin B1 (CCNB1; 123836)-CDK1 (116940), as well as timely breakdown of the nuclear envelope, histone H3 phosphorylation, and chromatin condensation. Expression of constitutively nuclear cyclin B1 abrogated many of these effects. In contrast with knockdown of cyclin A2, knockdown of cyclin B1, or, more potently, of both cyclins B1 and B2 (CCNB2; 602755), had more dramatic effects on later mitotic events. Gong and Ferrell (2010) hypothesized that cyclin A2 helps initiate mitosis, in part by activating cyclin B1-CDK1 activation and nuclear translocation.

Kabeche and Compton (2013) found that kinetochore-microtubule (k-MT) attachments in prometaphase cells are considerably less stable than in metaphase cells, and that the switch to more stable k-MT attachments in metaphase requires the proteasome-dependent destruction of cyclin A in prometaphase. Persistent cyclin A expression prevents k-MT stabilization even in cells with aligned chromosomes. By contrast, k-MTs are prematurely stabilized in cyclin A-deficient cells. Consequently, cells lacking cyclin A display higher rates of chromosome missegregation. Thus, the stability of k-MT attachments increases decisively in a coordinated fashion among all chromosomes as cells transit from prometaphase to metaphase. Cyclin A creates a cellular environment that promotes microtubule detachment from kinetochores in prometaphase to ensure efficient error correction and faithful chromosome segregation.

Liu et al. (2014) reported that AKT (164730) activity fluctuates across the cell cycle, mirroring CCNA2 expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase-2 (CDK2; 116953)/CCNA2 or mTORC2 (see 601231), under distinct physiologic conditions, promoted Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of both Ccna2 alleles in the mouse olfactory bulb led to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, Ccna2 deletion-induced cellular apoptosis in mouse embryonic stem cells was partly rescued by S477D/T479E-Akt1, supporting a physiologic role for Ccna2 in governing Akt activation. Liu et al. (2014) concluded that, taken together, the results of their study showed AKT S477/T479 phosphorylation to be an essential layer of the AKT activation mechanism to regulate its physiologic functions, thereby providing a mechanistic link between aberrant cell cycle progression and AKT hyperactivation in cancer.

Kanakkanthara et al. (2016) found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to upregulate the meiotic recombination-11 (MRE11; 600814) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. Kanakkanthara et al. (2016) concluded that their data revealed cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding-dependent role that ensures adequate repair of common replication errors.

The restriction (R) point marks the point in the cell cycle when cells become independent of mitogen signaling and CDK2 activity becomes self-sustaining through a feedback loop between cyclin A2/CDK2 and RB1 (614041), leading to an irreversible commitment to proliferation. Cornwell et al. (2023) demonstrated that mitogen signaling maintained CDK2 activity in S and G2 phases of the cell cycle, and that, in the absence of mitogen signaling, some post-R-point cells exited the cell cycle and entered a G0-like state instead of irreversibly committing to proliferation. Further analysis indicated that mitosis and cell cycle exit were 2 mutually exclusive fates, and that competition between the 2 determined whether cells continued to proliferate or exited the cell cycle. As a result, the decision to proliferate was fully reversible, even when cells were in post-R state, because CDK2 activation and RB1 phosphorylation were reversible in all post-R cells after loss of mitogen signaling. CDK4 (123829)/CDK6 (603368) promoted cyclin A2 synthesis in S/G2, and cyclin A2 stability was the primary contributor to cell cycle exit. Cells were dependent on mitogens and CDK4/CDK6 activity to maintain CDK2 activity and RB1 phosphorylation throughout the cell cycle. The R-point irreversibility phenomenon was observed in the absence of mitogens, because in most cells, the half-life of cyclin A2 was long enough to sustain CDK2 activity throughout G2/M to reach mitosis. The results implied that there is no single point when cells are irreversibly committed to proliferation that can be defined by a single molecular event, but rather that it is determined by the cell's proximity to mitosis, as well as the cyclin A2 level when mitogen signaling is lost.


Mapping

By in situ hybridization, Blanquet et al. (1990) mapped the CCNA gene to 4q26-q27. They pointed to the interest of this finding in connection with the demonstrated loss of heterozygosity for markers on 4q in tumor tissue of patients with liver cancer (Buetow et al., 1989). By genetic mapping using a cyclin A probe, Lock et al. (1992) demonstrated a single Cyca gene on mouse chromosome 3.


Molecular Genetics

For discussion of a possible association between variation in the CCNA2 gene and autosomal recessive intellectual developmental disorder-29 (614333), see 123835.0001.


Animal Model

The mammalian A-type cyclin family consists of 2 members, cyclin A1 (CCNA1; 604036) and cyclin A2 (CCNA2). Cyclin A2 promotes both G1/S and G2/M transitions (Pagano et al., 1992). Murphy et al. (1997) demonstrated that a targeted deletion of the murine Ccna2 gene is embryonically lethal, although homozygous null mutant embryos developed normally until postimplantation, approximately day 5.5 postcoitum. The authors suggested that the embryos survived either because a maternal pool of cyclin A2 protein persists until at least the blastocyst stage, or because cyclin A1 plays an unexpected role during early embryo development. In an erratum, the authors stated that maternal cyclin A2 cannot be considered to persist to the blastocyst stage during early mouse development. Cyclin A1 is expressed in mice exclusively in the germline lineage (Sweeney et al., 1996) and is expressed in humans at highest levels in the testis and certain myeloid leukemia cells (Yang et al., 1997).


ALLELIC VARIANTS 1 Selected Example):

.0001   VARIANT OF UNKNOWN SIGNIFICANCE

CCNA2, 1-BP INS
SNP: rs2149043311, ClinVar: RCV000255886

This variant is classified as a variant of unknown significance because its contribution to autosomal recessive intellectual developmental disorder-29 (MRT29; 614333) has not been confirmed.

In affected members of a consanguineous Iranian family (M346) with autosomal recessive intellectual developmental disorder mapped to chromosome 4q by Kuss et al. (2011), Najmabadi et al. (2011) identified homozygosity for a 1-bp deletion (chr4:122,963,253_122,963,254ins1) in the CCNA2 gene. No functional studies were performed.


REFERENCES

  1. Blanquet, V., Wang, J., Chenivesse, X., Henglein, B., Garreau, F., Brechot, C., Turleau, C. Assignment of a human cyclin A gene to 4q26-q27. Genomics 8: 595-597, 1990. [PubMed: 1962755] [Full Text: https://doi.org/10.1016/0888-7543(90)90052-v]

  2. Buetow, K. H., Murray, J. E., Israel, J. L., London, W. T., Smith, M., Kew, M., Blanquet, V., Brechot, C., Redeker, A., Govindarajah, S. Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc. Nat. Acad. Sci. 86: 8852-8856, 1989. [PubMed: 2573067] [Full Text: https://doi.org/10.1073/pnas.86.22.8852]

  3. Cornwell, J. A., Crncec, A., Afifi, M. M., Tang, K., Amin, R., Cappell, S. D. Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal. Nature 619: 363-370, 2023. [PubMed: 37407814] [Full Text: https://doi.org/10.1038/s41586-023-06274-3]

  4. Girard, F., Strausfeld, U., Fernandez, A., Lamb, N. J. C. Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67: 1169-1179, 1991. [PubMed: 1836977] [Full Text: https://doi.org/10.1016/0092-8674(91)90293-8]

  5. Gong, D., Ferrell, J. E., Jr. The roles of cyclin A2, B1, and B2 in early and late mitotic events. Molec. Biol. Cell 21: 3149-3161, 2010. [PubMed: 20660152] [Full Text: https://doi.org/10.1091/mbc.E10-05-0393]

  6. Henglein, B., Chenivesse, X., Wang, J., Eick, D., Brechot, C. Structure and cell cycle-regulated transcription of the human cyclin A gene. Proc. Nat. Acad. Sci. 91: 5490-5494, 1994. [PubMed: 8202514] [Full Text: https://doi.org/10.1073/pnas.91.12.5490]

  7. Hunter, T., Pines, J. Cyclins and cancer. Cell 66: 1071-1074, 1991. [PubMed: 1833062] [Full Text: https://doi.org/10.1016/0092-8674(91)90028-w]

  8. Kabeche, L., Compton, D. A. Cyclin A regulates kinetochore microtubules to promote faithful chromosome segregation. Nature 502: 110-113, 2013. [PubMed: 24013174] [Full Text: https://doi.org/10.1038/nature12507]

  9. Kanakkanthara, A., Jeganathan, K. B., Limzerwala, J. F., Baker, D. J., Hamada, M., Nam, H.-J., van Deursen, W. H., Hamada, N., Naylor, R. M., Becker, N. A., Davies, B. A., van Ree, J. H., Mer, G., Shapiro, V. S., Maher, L. J., III, Katzmann, D. J., van Deursen, J. M. Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation. Science 353: 1549-1552, 2016. [PubMed: 27708105] [Full Text: https://doi.org/10.1126/science.aaf7463]

  10. Kuss, A. W., Garshasbi, M., Kahrizi, K., Tzschach, A., Behjati, F., Darvish, H., Abbasi-Moheb, L., Puettmann, L., Zecha, A., Weissmann, R., Hu, H., Mohseni, M., and 18 others. Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots. Hum. Genet. 129: 141-148, 2011. [PubMed: 21063731] [Full Text: https://doi.org/10.1007/s00439-010-0907-3]

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Contributors:
Bao Lige - updated : 02/08/2024
Ada Hamosh - updated : 12/21/2016
Carol A. Bocchini - updated : 10/05/2016
Patricia A. Hartz - updated : 7/22/2014
Ada Hamosh - updated : 5/30/2014
Ada Hamosh - updated : 12/5/2013
Rebekah S. Rasooly - updated : 7/21/1999
Victor A. McKusick - updated : 11/30/1998

Creation Date:
Victor A. McKusick : 2/27/1990

Edit History:
mgross : 02/08/2024
carol : 04/07/2022
alopez : 12/21/2016
carol : 10/10/2016
carol : 10/05/2016
mgross : 10/10/2014
mcolton : 7/22/2014
alopez : 5/30/2014
alopez : 12/5/2013
carol : 12/17/2012
alopez : 2/23/2011
terry : 5/20/2010
terry : 1/22/2001
mgross : 7/21/1999
dkim : 12/2/1998
alopez : 12/1/1998
terry : 11/30/1998
carol : 6/28/1994
jason : 6/22/1994
carol : 3/9/1993
carol : 6/24/1992
supermim : 3/16/1992
carol : 2/17/1992