Cyclin-A2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''CCNA2''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
It is one of the two types of
cyclin A
Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cel ...
:
cyclin A1
Cyclin-A1 is a protein that in humans is encoded by the ''CCNA1'' gene.
Function
The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance thro ...
is expressed during meiosis and embryogenesis while cyclin A2 is expressed in dividing somatic cells.
Function
Cyclin A2 belongs to the
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.
Etymology
Cyclins were originally disco ...
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
Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the ''CDK2'' gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein ...
during S phase, and
CDK1
Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in th ...
during the transition from G2 to M phase.
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
Cell division control protein 6 homolog is a protein that in humans is encoded by the ''CDC6'' gene.
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. ...
and
MCM4
DNA replication licensing factor MCM4 is a protein that in humans is encoded by the ''MCM4'' gene.
Function
The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the i ...
by the cyclin A2-CDK2 complex prevents re-replication of DNA during the cell cycle.
Cyclin A2 is involved in the G2/M transition but it cannot independently form a
maturation promoting factor
Maturation-promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-Phase-promoting factor) is the cyclin-Cdk complex that was discovered first in frog eggs. It stimulates the mitotic and meiotic phases of the cell cycle. MPF ...
(MPF).
Recent studies have shown that the cyclin A2-CDK1 complex triggers
cyclin B1
G2/mitotic-specific cyclin-B1 is a protein that in humans is encoded by the ''CCNB1'' gene.
Function
Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34 (Cdk1) to form the maturation-promoting factor (MPF) ...
-CDK1 activation which results in chromatin condensation and the breakdown of the nuclear envelope.
Regulation
The levels of cyclin A2 are tightly synchronized with the progression of the cell cycle.
Transcription initiates in late G1, peaks and plateaus in mid-S, and declines in G2.
Cyclin A2 transcription is mostly regulated by the transcription factor
E2F and begins in G1, after the
R point
''R-Point'' () is a 2004 South Korean psychological horror War film, wartime film written and directed by Kong Su-chang. Set in Vietnam in 1972, during the Vietnam War, it stars Kam Woo-sung and Son Byong-ho as members of the Military history of S ...
.
Absence of cyclin A2 before the R point is due to the E2F inhibition by hypophosphorylated
retinoblastoma protein
The retinoblastoma protein (protein name abbreviated pRb; gene name abbreviated ''Rb'', ''RB'' or ''RB1'') is a proto-oncogenic tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive ...
(pRb). After the R point, pRb is phosphorylated and can no longer bind E2F, leading to cyclin A2 transcription.
The cyclin A2-CDK2 complex eventually phosphorylates E2F, turning off cyclin A2 transcription.
E2F promotes cyclin A2 transcription by de-repressing the promoter.
Interactions
Cyclin A2 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
CDC6
Cell division control protein 6 homolog is a protein that in humans is encoded by the ''CDC6'' gene.
The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Cdc6, a protein essential for the initiation of DNA replication. ...
,
*
E2F1
Transcription factor E2F1 is a protein that in humans is encoded by the ''E2F1'' gene.
Function
The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell ...
,
*
FEN1
Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene.
Function
The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases a ...
,
*
ITGB3BP
Centromere protein R is a protein that in humans is encoded by the ''ITGB3BP'' gene.
Interactions
ITGB3BP has been shown to interact with:
* CD61,
* Cyclin A2,
* NFKB1,
* RXRA,
* RXRG, and
* THRA
Thyroid hormone receptor alpha (TR-alpha) als ...
,
*
RBL1,
and
*
SKP2
S-phase kinase-associated protein 2 is an enzyme that in humans is encoded by the ''SKP2'' gene.
Structure and function
Skp2 contains 424 residues in total with the ~40 amino acid F-box domain lying closer to the N-terminal region at the 94-1 ...
.
DNA Repair
Cyclin A2 regulates
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
in human breast cancer cells
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
Double-strand break repair protein MRE11 is an enzyme that in humans is encoded by the ''MRE11'' gene. The gene has been designated ''MRE11A'' to distinguish it from the pseudogene ''MRE11B'' that is nowadays named ''MRE11P1''.
Function
This ge ...
and
RAD51
DNA repair protein RAD51 homolog 1 is a protein encoded by the gene ''RAD51''. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to th ...
DNA repair proteins.
[ Cyclin A2 mediates the abundance of MRE11 nuclease by binding to ''Mre11'' mRNA. Cyclin A2 mediates the abundance of RAD51 protein by inhibiting ]proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
degradation of this protein.
During mouse development and aging, cyclin A2 promotes DNA repair, particularly double-strand break repair, in the brain. Also in mice, cyclin A2 was found to be an RNA binding protein that controls the translation of ''Mre11'' mRNA.
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. 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. 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. Delivery of Ccna2 into cardiac tissue invokes a regenerative response and markedly enhances cardiac function.
Cancer
Increased expression of cyclin A2 has been observed in many types of cancer such as breast, cervical, liver, and lung among others. While it is not clear whether increased expression of cyclin A2 is a cause or result of tumorigenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
, it is indicative of prognostic values such as predictions of survival or relapse.
Overexpression of cyclin A2 in mammalian cells can result in the delayed onset of metaphase
Metaphase ( and ) is a stage of mitosis in the eukaryotic cell cycle in which chromosomes are at their second-most condensed and coiled stage (they are at their most condensed in anaphase). These chromosomes, carrying genetic information, align ...
and anaphase
Anaphase () is the stage of mitosis after the process of metaphase, when replicated chromosomes are split and the newly-copied chromosomes (daughter chromatids) are moved to opposite poles of the cell. Chromosomes also reach their overall maxim ...
. It is also possible that cyclin A2-CDK contributes to tumorigenesis by the phosphorylation of oncoproteins
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. or tumor suppressors like p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
.
See also
*Cyclin A
Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cel ...
References
Further reading
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{{Cell cycle proteins
Cell cycle regulators