G1/S transition

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Depiction of regulation at the G1/S transition point in cell cycle progression. Figure taken from 2A of https://dx.doi.org/10.1016/j.cels.2016.01.001 Author credit: Alexis R. Barr, Frank S. Heldt, Tongli Zhang, Chris Bakal, and Be la Nova G1-S cell cycle regulation.jpg
Depiction of regulation at the G1/S transition point in cell cycle progression. Figure taken from 2A of https://dx.doi.org/10.1016/j.cels.2016.01.001 Author credit: Alexis R. Barr, Frank S. Heldt, Tongli Zhang, Chris Bakal, and Be ́ la Nova ́
Cell cycle Cell Cycle 2-2.svg
Cell cycle
Signal transduction pathways influencing gene regulation and cellular proliferation. Signal transduction v1.png
Signal transduction pathways influencing gene regulation and cellular proliferation.

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. [1] 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. [2] During this transition the cell makes decisions to become quiescent (enter G0), differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. [3] 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. [4] [1]

Contents

During this transition, G1 cyclin D-Cdk4/6 dimer phosphorylates retinoblastoma releasing transcription factor E2F, which then drives the transition from G1 to S phase. The G1/S transition is highly regulated by transcription factor p53 in order to halt the cell cycle when DNA is damaged. [5]

It is a "point of no return" beyond which the cell is committed to dividing; in yeast this is called the Start point, and in multicellular eukaryotes it is termed the restriction point (R-Point). [2] [6] If a cell passes through the G1/S transition the cell will continue through the cell cycle regardless of incoming mitogenic factors due to the positive feed-back loop of G1-S transcription. [2] Positive feed-back loops include G1 cyclins and accumulation of E2F. [2]

Cell cycle overview

The cell cycle is a process in which an ordered set of events leads to the growth and division into two daughter cells. The cell cycle is a cycle rather than a linear process because the two daughter cells produced repeat the cycle. This process contains two main phases, interphase, in which the cell grows and synthesizes a copy of its DNA, and the mitotic (M) phase, during which the cell separates its DNA and divides into two new daughter cells. [7] Interphase is further broken down into the G1 (GAP 1) phase, S (Synthesis) phase, G2 (GAP 2) phase and the mitotic (M) phase which in turn is broken down into mitosis and cytokinesis. Following cytokinesis, during G1 phase the cells monitor environment for the potential growth factors, grow larger and once achieve the threshold size (rRNA and overall protein content characteristic for a given cell type) they start progression through S phase. [8] During S phase, the cell also duplicates the centrosome, or microtubule-organizing center, which is critical for DNA separation in the M phase. After complete synthesis of its DNA, the cell enters the G2 phase where it continues to grow in preparation for mitosis. Following interphase, the cell transitions into mitosis, containing four sub stages: prophase, anaphase, metaphase, and telophase. In mitosis, DNA condenses into chromosomes, which are lined up and separated by the mitotic spindle. [9] After duplicate DNA is separated on opposite ends of the cell, the cytoplasm of the cell is split in two during cytokinesis resulting in two daughter cells. [7]

Cell cycle regulation

As with most processes in the body, the cell cycle is highly regulated to prevent the synthesis of mutated cells and uncontrolled cell division that leads to tumor formation. [10] The cell cycle control system is biochemically based so that the proteins of the mitosis promoting factor (MPF) control the transition from one phase to the next based on a series of checkpoints. MPF is a protein dimer made up of cyclin and cyclin-dependent kinase (Cdk), a serine and threonine kinase, which come together at different points in the cycle to control cell progression through the cycle. When cyclin binds to Cdk, Cdk becomes activated and phosphorylates serine and threonine on other proteins causing the activation and degradation of other proteins allowing the cell to transition through the cell cycle. [7]

G1/transition

In mid to late G1 phase, cyclin D bound to Cdk4/6, activates the expression of the S phase cyclin-Cdk components; however, the cell does not want S phase cyclins to become active in G1. [7] Therefore, an inhibitor, protein Slc-1, is present that interacts with the dimer so that the S phase cyclin-Cdk dimer remains inactive until the cell is ready to move into S phase. [7] After the cell has grown and is ready to synthesize DNA, G1 cyclin-Cdks phosphorylate the S phase cyclin inhibitor signaling ubiquitination, resulting in the addition of groups to the inhibitor. Ubiquitination of the inhibitor signals the SCF/proteasome to degrade the inhibitor releasing and allowing the S phase cyclin-Cdk to become activated and the cell moves into S phase. Once in S phase, cyclin-Cdks phosphorylate several factors on the replication complex promoting DNA replication by causing inhibitory proteins to fall off of replication complexes or through activation of components on the replication complex to induce DNA replication initiation. [11]

Retinoblastoma protein (pRB) and the G1/S transition

Crystal structure of the retinoblastoma tumour suppressor protein bound to E2F RB1.JPG
Crystal structure of the retinoblastoma tumour suppressor protein bound to E2F

Another dimer present during mid G1 is composed of retinoblastoma protein (pRB) and transcription factor E2F. When pRb is bound to E2F, E2F is inactive. As cyclin D is synthesized and activates Cdk4/6, the cyclin-Cdk targets Rb protein for phosphorylation. Upon phosphorylation, pRb changes conformation so that E2F is released and activated, binding to upstream regions of genes, initiating expression. Specifically, E2F drives the expression of other cyclins, including cyclin E and A, and genes necessary for DNA replication. Cyclin E either phosphorylates more pRb to further activate E2F and promote the expression of more Cyclin E, or it has the ability to increase expression of itself. Cyclin E also interacts with Cdk2 driving the cell cycle to progress from G1 to S phase. [12]

The role of retinoblastoma in tumor formation

Retinoblastoma (Rb) is a cancer of the eye due to a mutant pRb protein. [7] When pRb is mutated it becomes nonfunctional and is not able to inhibit the expression of transcription factor E2F. Therefore, E2F is always active and driving the cell cycle to progress from G1 to S phase. As a result, cell growth and division is unregulated causing tumor formation in the eye. [10]

Cell cycle checkpoints

To ensure proper cell division, the cell cycle utilizes numerous checkpoints to monitor cell progression and halt the cycle when processes go awry. These checkpoints include four DNA damage checkpoints, one unreplicated DNA checkpoint at the end of G2, one spindle assembly checkpoint in mitosis, and a chromosome segregation checkpoint during mitosis. [10]

p53 as a regulator

Conceptualization of p53 pathway. P53 Pathway.png
Conceptualization of p53 pathway.
p53-DNA damage complex Tumour suppressor p53-DNA complex.jpg
p53-DNA damage complex

Between G1 and S phase, three DNA damage checkpoints occur to ensure proper growth and synthesis of DNA prior to cell division. Damaged DNA during G1, before entry into S phase, and during S phase result in the expression of ATM/R protein. ATM/R protein then stabilizes and activates transcription factor p53 so that it can bind to upstream regions of genes, inducing the expression of proteins including p21CIP. p21CIP binds to and inhibits any cyclin-cdk present in the cell cycle, halting the cycle until DNA damage can be corrected. [13]

Additional processes at DNA damage checkpoints

Of the four DNA damage checkpoints, two have an additional process for monitoring DNA damage other than activating p53. Before entry into S phase and during S phase, ATM/R also activates Chk1/2 that inhibits Cdc25A, a protein responsible for activating cyclin-Cdk dimers. Without cyclin dimer activation, the cell cannot transition through the cycle. These two checkpoints have additional processes for regulation because replicating damaged DNA in S phase can be deleterious to the cell and more importantly, the organism. [7]

See also

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.

G<sub>1</sub> phase First growth phase in the eukaryotic cell cycle

The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes mRNA and proteins in preparation for subsequent steps leading to mitosis. G1 phase ends when the cell moves into the S phase of interphase. Around 30 to 40 percent of cell cycle time is spent in the G1 phase.

G<sub>0</sub> phase Quiescent stage of the cell cycle in which the cell does not divide

The G0 phase describes a cellular state outside of the replicative cell cycle. Classically, cells were thought to enter G0 primarily due to environmental factors, like nutrient deprivation, that limited the resources necessary for proliferation. Thus it was thought of as a resting phase. G0 is now known to take different forms and occur for multiple reasons. For example, most adult neuronal cells, among the most metabolically active cells in the body, are fully differentiated and reside in a terminal G0 phase. Neurons reside in this state, not because of stochastic or limited nutrient supply, but as a part of their developmental program.

<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.

<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.

The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.

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 cell cycle 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.

<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.

<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> Protein-coding gene in the species Homo sapiens

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

<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 dividing 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.

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in Homo sapiens

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

<span class="mw-page-title-main">DNA re-replication</span> Undesirable occurrence in eukaryotic cells

DNA re-replication is an undesirable and possibly fatal occurrence in eukaryotic cells in which the genome is replicated more than once per cell cycle. Rereplication is believed to lead to genomic instability and has been implicated in the pathologies of a variety of human cancers. To prevent rereplication, eukaryotic cells have evolved multiple, overlapping mechanisms to inhibit chromosomal DNA from being partially or fully rereplicated in a given cell cycle. These control mechanisms rely on cyclin-dependent kinase (CDK) activity. DNA replication control mechanisms cooperate to prevent the relicensing of replication origins and to activate cell cycle and DNA damage checkpoints. DNA rereplication must be strictly regulated to ensure that genomic information is faithfully transmitted through successive generations.

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.

References

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  5. ↑ Lodish H, Berk A, Kaiser C, Krieger M (2012). Molecular Cell Biology (7th ed.). Freeman, W. H. & Company. ISBN   978-1-4641-0981-2.
  6. ↑ Tenga MJ, Lazar IM (January 2013). "Proteomic snapshot of breast cancer cell cycle: G1/S transition point". Proteomics. 13 (1): 48–60. doi:10.1002/pmic.201200188. PMC   4123745 . PMID   23152136.
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  9. ↑ "Phases of the Cell Cycle". KhanAcademy. KhanAcademy.
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  11. ↑ Poli A (2015). New DAG-dependent mechanisms modulate cell cycle progression [Dissertation]. Scienze Biomediche (Doctoral Thesis). doi:10.6092/unibo/amsdottorato/6739.
  12. ↑ Fadila G, Jinho H, Vaddadi N, Abbas T (2015). "Novel regulation of cyclin D1 stability and the DNA damage response". Proceedings of the 106th Annual Meeting of the American Association for Cancer Research. 75 (15 Supplement): 3786. doi:10.1158/1538-7445.AM2015-3786.
  13. ↑ Wang X, Simpson ER, Brown KA (December 2015). "p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis". Cancer Research. 75 (23): 5001–7. doi:10.1158/0008-5472.CAN-15-0563. PMID   26573797.
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