Cyclin A

Last updated
cyclin A1
Identifiers
Symbol CCNA1
NCBI gene 8900
HGNC 1577
OMIM 604036
RefSeq NM_003914
UniProt P78396
Other data
Locus Chr. 13 q12.3-q13
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Structures Swiss-model
Domains InterPro
cyclin A2
Identifiers
Symbol CCNA2
Alt. symbolsCCNA, CCN1
NCBI gene 890
HGNC 1578
OMIM 123835
RefSeq NM_001237
UniProt P20248
Other data
Locus Chr. 4 q27
Search for
Structures Swiss-model
Domains InterPro

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. [1] The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle [2] Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages. [1] [3]

Contents

Types

Cyclin A was first identified in 1983 in sea urchin embryos. [4] Since its initial discovery, homologues of cyclin A have been identified in numerous eukaryotes including Drosophila , [5] Xenopus , mice, and in humans but has not been found in lower eukaryotes like yeast. [6] [7] The protein exists in both an embryonic form and somatic form. A single cyclin A gene has been identified in Drosophila while Xenopus, mice and humans contain two distinct types of cyclin A: A1, the embryonic-specific form, and A2, the somatic form. Cyclin A1 is prevalently expressed during meiosis and early on in embryogenesis. Cyclin A2 is expressed in dividing somatic cells. [7]

Role in cell cycle progression

Expression of human cyclins through the cell cycle Cyclin Expression.svg
Expression of human cyclins through the cell cycle

Cyclin A, along with the other members of the cyclin family, regulates cell cycle progression through physically interacting with cyclin-dependent kinases (CDKs), [8] [9] which thereby activates the enzymatic activity of its CDK partner. [1] [2] [8]

CDK partner association

The interaction between the cyclin box, a region conserved across cyclins, and a region of the CDK, called the PSTAIRE, confers the foundation of the cyclin-CDK complex. [10] Cyclin A is the only cyclin that regulates multiple steps of the cell cycle. [7] Cyclin A can regulate multiple cell cycle steps because it associates with, and thereby activates, two distinct CDKs – CDK2 and CDK1. [1] Depending on which CDK partner cyclin A binds, the cell will continue through the S phase or it will transition from G2 to the M phase. [1] [3] [10] Association of cyclin A with CDK2 is required for passage into S phase while association with CDK1 is required for entry into M phase. [10]

S phase

Cyclin A resides in the nucleus during S phase where it is involved in the initiation and completion of DNA replication. [1] [6] [9] As the cell passes from G1 into S phase, cyclin A associates with CDK2, replacing cyclin E. Cyclin E is responsible for initiating the assembly of the pre-replication complex. This complex makes chromatin capable of replication. When the amount of cyclin A/CDK2 complex reaches a threshold level, it terminates the assembly of the pre-replication complex made by cyclin E/CDK2. As the amount of Cyclin A/CDK2 complex increases, the complex initiates DNA replication. [11]

Cyclin A has a second function in S phase. In addition to initiating DNA synthesis, Cyclin A ensures that DNA is replicated once per cell cycle by preventing the assembly of additional replication complexes. [7] [11] [12] This is thought to occur through the phosphorylation of particular DNA replication machinery components, such as CDC6, by the cyclin A/CDK2 complex. [1] [7] Since the action of cyclin A/CDK2 inhibits that of cyclin E/CDK2, the sequential activation of cyclin E followed by the activation of cyclin A is important and tightly regulated in S phase. [7] [11]

G2 / M phase

In late S phase, cyclin A can also associate with CDK1. [1] [2] [7] Cyclin A remains associated with CDK1 from late S into late G2 phase when it is replaced by cyclin B. Cyclin A/CDK1 is thought to be involved in the activation and stabilization of cyclin B/CDK1 complex. [7] [8] Once cyclin B is activated, cyclin A is no longer needed and is subsequently degraded through the ubiquitin pathway. [3] [7] Degradation of cyclin A/CDK1 induces mitotic exit. [7]

Cyclin A/CDK2 complex was thought to be restricted to the nucleus and thus exclusively involved in S phase progression. New research has since debunked this assumption, shedding light on cyclin A/CDK2 migration to the centrosomes in late G2. [1] [8] Cyclin A binds to the mitotic spindle poles in the centrosome however, the mechanism by which the complex is shuttled to the centrosome is not well understood. It is suspected that the presence of cyclin A/CDK2 at the centrosomes may confer a means of regulating the movement of cyclin B/CDK1 to the centrosome and thus the timing of mitotic events. [1] [6] [8]

A study in 2008 [8] provided further evidence of cyclin A/CDK2 complex's role in mitosis. Cells were modified so their CDK2 was inhibited and their cyclin A2 gene was knocked out. These mutants entered mitosis late due to a delayed activation of the cyclin B/CDK1 complex. Coupling of microtubule nucleation in the centrosome with mitotic events in the nucleus was lost in the cyclin A knockout/CDK2 inhibited mutant cells.

Cyclin A has been shown to play a crucial role in the G2/M transition in Drosophila and Xenopus embryos. [3] [6]

Regulation

Transcription of cyclin A is tightly regulated and synchronized with cell cycle progression. [2] [3] Initiation of transcription of cyclin A is coordinated with passage of the R point, [2] a critical transition point that is required for progression from G1 into S phase. Transcription peaks and plateaus mid-S phase and abruptly declines in late G2. [7] [12]

E2F and pRb

Transcription of cyclin A is predominantly regulated by the transcription factor E2F in a negative feedback loop. E2F is responsible for initiating the transcription of many critical S phase genes. [1] [3] [6] Cyclin A transcription is off during most of G1 and the begins shortly after the R point. [3] [7]

The retinoblastoma protein (pRb) is involved in the regulation of cyclin A through its interaction with E2F. It exists in two states: hypophosphorylated pRb and hyperphosphorylated pRb. [2] Hypophosphorylated pRb binds E2F, which prevents transcription of cyclin A. The absence of cyclin A prior to the R point is due to the inhibition of E2F by hypophosphorylated pRb. After the cell passes through the R point, cyclin D/E- complexes phosphorylate pRb. Hyperphosphorylated pRb can no longer bind E2F, E2F is released and cyclin A genes, and other crucial genes for S phase, are transcribed. [2] [9] [12]

E2F initiates transcription of cyclin A by de-repressing the promoter. [7] [12] The promoter is bound by a repressor molecule called the cell-cycle-responsive element (CCRE). E2F binds to an E2F binding site on the CCRE, releasing the repressor from the promoter and allowing the transcription of cyclin A. [5] [7] Cyclin A/CDK2 will eventually phosphorylate E2F when cyclin A reaches a certain level, completing the negative feedback loop. Phosphorylation of E2F turns the transcription factor off, providing another level of controlling the transcription of cyclin A. [7]

p53 and p21

Transcription of cyclin A is indirectly regulated by the tumor suppressor protein p53. P53 is activated by DNA damage and turns on several downstream pathways, including cell cycle arrest. Cell cycle arrest is carried out by the p53-pRb pathway. [13] Activated p53 turns on genes for p21. P21 is a CDK inhibitor that binds to several cyclin/CDK complexes, including cyclin A-CDK2/1 and cyclin D/CDK4, and blocks the kinase activity of CDKs. [9] [13] Activated p21 can bind cyclin D/CDK4 and render it incapable of phosphorylating pRb. PRb remains hypophosphorylated and binds E2F. E2F is unable to activate the transcription of cyclins involved in cell cycle progression, such as cyclin A and the cell cycle is arrested at G1. [6] [13] Cell cycle arrest allows the cell to repair DNA damage before the cell divides and passes damaged DNA to daughter cells.

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Cyclin</span> Group of proteins

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.

<span class="mw-page-title-main">Cyclin-dependent kinase complex</span>

A cyclin-dependent kinase complex is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins.

<span class="mw-page-title-main">S phase</span> DNA replication phase of the cell cycle, between G1 and G2 phase

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

G<sub>2</sub> phase Second growth phase in the eukaryotic cell cycle, prior to mitosis

G2 phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G2 phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

<span class="mw-page-title-main">Restriction point</span> Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

E2F is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes. Three of them are activators: E2F1, 2 and E2F3a. Six others act as suppressors: E2F3b, E2F4-8. All of them are involved in the cell cycle regulation and synthesis of DNA in mammalian cells. E2Fs as TFs bind to the TTTCCCGC consensus binding site in the target promoter sequence.

Endoreduplication is replication of the nuclear genome in the absence of mitosis, which leads to elevated nuclear gene content and polyploidy. Endoreplication can be understood simply as a variant form of the mitotic cell cycle (G1-S-G2-M) in which mitosis is circumvented entirely, due to modulation of cyclin-dependent kinase (CDK) activity. Examples of endoreplication characterized in arthropod, mammalian, and plant species suggest that it is a universal developmental mechanism responsible for the differentiation and morphogenesis of cell types that fulfill an array of biological functions. While endoreplication is often limited to specific cell types in animals, it is considerably more widespread in plants, such that polyploidy can be detected in the majority of plant tissues.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

<span class="mw-page-title-main">Cyclin E</span> Member of the cyclin family

Cyclin E is a member of the cyclin family.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

<span class="mw-page-title-main">Cyclin-dependent kinase 2</span> Protein-coding gene in the species Homo sapiens

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 kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.

<span class="mw-page-title-main">Cyclin-dependent kinase 1</span> Mammalian protein found in Homo sapiens

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 the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<span class="mw-page-title-main">Cyclin A2</span> Protein-coding gene in the species Homo sapiens

Cyclin-A2 is a protein that in humans is encoded by the CCNA2 gene. 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.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

The Neuronal cell cycle represents the life cycle of the biological cell, its creation, reproduction and eventual death. The process by which cells divide into two daughter cells is called mitosis. Once these cells are formed they enter G1, the phase in which many of the proteins needed to replicate DNA are made. After G1, the cells enter S phase during which the DNA is replicated. After S, the cell will enter G2 where the proteins required for mitosis to occur are synthesized. Unlike most cell types however, neurons are generally considered incapable of proliferating once they are differentiated, as they are in the adult nervous system. Nevertheless, it remains plausible that neurons may re-enter the cell cycle under certain circumstances. Sympathetic and cortical neurons, for example, try to reactivate the cell cycle when subjected to acute insults such as DNA damage, oxidative stress, and excitotoxicity. This process is referred to as “abortive cell cycle re-entry” because the cells usually die in the G1/S checkpoint before DNA has been replicated.

<span class="mw-page-title-main">Cyclin E/Cdk2</span>

The Cyclin E/Cdk2 complex is a structure composed of two proteins, cyclin E and cyclin-dependent kinase 2 (Cdk2). Similar to other cyclin/Cdk complexes, the cyclin E/Cdk2 dimer plays a crucial role in regulating the cell cycle, with this specific complex peaking in activity during the G1/S transition. Once the two cyclin and Cdk subunits are joined together, the complex becomes activated and proceeds to phosphorylate and bind to downstream proteins to ultimately promote cell cycle progression. Although cyclin E can bind to other Cdk proteins, its primary binding partner is Cdk2, and the majority of cyclin E activity occurs when it exists as the cyclin E/Cdk2 complex.

References

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