GO:0044772 mitotic cell cycle phase transition: Regulation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0044772 (mitotic cell cycle phase transition) describes the commitment step by which a cell enters the next phase of the mitotic cell cycle, including G1/S, G2/M and metaphase-to-anaphase transitions.
• Phase transitions are driven by cyclin-dependent kinases (CDKs), their cyclin partners (e.g., CCNA2, CCNB1), and checkpoint kinases such as PLK1 and CDC25C.
• Checkpoint control at mitotic exit ensures that chromosome segregation and cytokinesis occur only after proper spindle assembly and DNA integrity.
• Mitotic chromatin undergoes a material phase transition that prevents microtubule perforation, linking biophysical properties to cell cycle progression.
• Dysregulation of mitotic phase transitions is a hallmark of cancer; expression-based nomograms of mitotic cell cycle genes predict overall survival in lung adenocarcinoma.
• Caspases and p21(WAF1/CIP1) can modulate cell cycle progression at mitotic phases, revealing crosstalk between apoptosis and cell cycle machinery.
Description
The mitotic cell cycle phase transition (GO:0044772) is a fundamental biological process that governs the ordered progression of a cell through the mitotic cell cycle. It encompasses the commitment points at which a cell irreversibly enters the next phase, such as G1 to S, G2 to M, and metaphase to anaphase. This process ensures that DNA replication, chromosome segregation, and cell division occur with high fidelity, and its deregulation is associated with genomic instability and cancer. Researchers study this term to understand how cells integrate internal and external signals to make fate decisions, and to identify therapeutic targets that selectively kill proliferating cells. The transition is not a single event but a series of tightly regulated checkpoints that coordinate cyclin-dependent kinase (CDK) activity, ubiquitin-mediated proteolysis, and cytoskeletal dynamics. For example, the G2/M transition requires the activation of CDK1-cyclin B complexes, which is controlled by CDC25C phosphatase and PLK1 kinase. Additionally, recent work has revealed that mitotic chromosomes undergo a material phase transition that alters their mechanical properties, preventing perforation by microtubules during segregation. These findings highlight that phase transitions are both biochemical and biophysical in nature. In this article, we provide a comprehensive overview of GO:0044772, covering its definition, key genes, regulatory mechanisms, disease associations, and experimental models for research.
mitotic cell cycle phase transition At A Glance
| GO ID | GO:0044772 |
|---|---|
| GO term | mitotic cell cycle phase transition |
| Ontology | biological_process |
| Synonym | none |
| Major function | Commitment of a cell to enter the next phase of the mitotic cell cycle, ensuring ordered progression through G1, S, G2, and M phases. |
| Key regulators | CDKs, cyclins (e.g., CCNA2, CCNB1), CDC25C, PLK1, and checkpoint kinases. |
| Associated diseases | Cancer, including lung adenocarcinoma, where mitotic cell cycle gene expression predicts survival. |
| Biophysical aspect | Mitotic chromatin undergoes a phase transition that prevents microtubule perforation. |
| Research methods | CRISPR knockout/knock-in, live-cell imaging, phosphoproteomics, and transcriptomic nomograms. |
What Is GO:0044772?
According to the Gene Ontology, GO:0044772 (mitotic cell cycle phase transition) is defined as the cell cycle process by which a cell commits to entering the next mitotic cell cycle phase. In other words, it is the point of no return at which a cell decides to progress from one phase of the mitotic cycle to the next, such as from G1 to S phase or from G2 to M phase. This commitment involves the activation of specific CDK-cyclin complexes and the inactivation of inhibitory checkpoints, ensuring that the next phase begins only when the previous one is complete.
Why Is mitotic cell cycle phase transition Important in Cell Biology?
Understanding GO:0044772 is critical because the commitment to enter the next mitotic phase is a decisive step that, when deregulated, leads to uncontrolled proliferation, genomic instability, and cancer. Many chemotherapeutic agents target components of these transitions, such as CDK inhibitors and spindle poisons, making this process a prime therapeutic target. Moreover, the biophysical properties of mitotic chromosomes during phase transitions influence the fidelity of chromosome segregation, and defects can cause aneuploidy. Therefore, studying this term provides insights into both basic cell biology and disease mechanisms.
• Deregulation of mitotic phase transitions is a hallmark of cancer, driving uncontrolled proliferation.
• Checkpoint control at these transitions ensures genomic stability; failure leads to aneuploidy and tumorigenesis.
• CDK-cyclin complexes that govern phase transitions are validated drug targets in oncology.
• The G2/M transition is a metabolic checkpoint regulated by AMPK, linking cellular energy status to cell cycle progression.
• Caspases can influence mitotic phase transitions, revealing crosstalk between apoptosis and cell cycle.
• p21(WAF1/CIP1) modulates cell cycle progression at G2/M following stress, affecting cell fate.
• Cyclin A2 localization at the S/G2 transition activates PLK1, a key mitotic kinase.
• Mitotic chromatin material properties change during phase transitions, impacting chromosome segregation fidelity.
• Expression signatures of mitotic cell cycle genes can predict overall survival in lung adenocarcinoma.
• Understanding phase transitions aids in the development of targeted therapies that selectively kill dividing cells.
What Happens During mitotic cell cycle phase transition?
G1/S Transition
In simple terms: The cell decides to copy its DNA and get ready to divide.
The G1/S transition is a commitment point where the cell irreversibly enters S phase and initiates DNA replication. This transition is driven by the activation of CDK2-cyclin E complexes, which phosphorylate the retinoblastoma protein (RB), releasing E2F transcription factors that activate genes required for DNA synthesis. Checkpoint kinases such as ATM/ATR can delay this transition in response to DNA damage, allowing repair before replication. In Saccharomyces cerevisiae, the G1/S transition is controlled by the Cln3-Cdc28 complex and the Swi4/Swi6 transcription factors, highlighting conserved mechanisms.
G2/M Transition
In simple terms: The cell checks that everything is ready and then starts mitosis.
The G2/M transition is the point at which the cell enters mitosis. It requires the activation of CDK1-cyclin B complexes, which are kept inactive by inhibitory phosphorylation on CDK1 (Tyr15) until dephosphorylated by CDC25C phosphatase. PLK1 kinase further activates CDC25C, creating a positive feedback loop that ensures rapid mitotic entry. The AMP-activated protein kinase (AMPK) can phosphorylate CDC25C, mediating a metabolic checkpoint that delays G2/M under low energy conditions. Cyclin A2 localizes to the cytoplasm at the S/G2 transition to activate PLK1, linking S phase completion to mitotic entry.
Metaphase-to-Anaphase Transition
In simple terms: The cell makes sure all chromosomes are attached before pulling them apart.
The metaphase-to-anaphase transition is triggered by the spindle assembly checkpoint (SAC), which monitors kinetochore-microtubule attachments. Once all chromosomes are properly bi-oriented, the SAC is silenced, allowing the anaphase-promoting complex/cyclosome (APC/C) to ubiquitinate securin and cyclin B, leading to separase activation and sister chromatid separation. In budding yeast, the mitotic exit network (MEN) coordinates this transition with cytokinesis. Defects in this transition cause chromosome mis-segregation and aneuploidy.
Mitotic Chromatin Phase Transition
In simple terms: During mitosis, chromosomes change their physical state to become stiff and resistant to penetration.
Recent studies have revealed that mitotic chromosomes undergo a material phase transition that alters their mechanical properties, making them resistant to perforation by microtubules. This transition involves changes in chromatin compaction and the recruitment of specific proteins, such as condensins and topoisomerase II, which modify the viscoelastic properties of chromosomes. The phase transition is thought to protect the genome during segregation and ensure proper chromosome mechanics.
Caspase and p21 Modulation of Mitotic Transitions
In simple terms: Proteins involved in cell death can also influence how cells progress through mitosis.
Caspases, traditionally known for apoptosis, can modulate cell cycle regulation at mitotic phases. For example, caspase activity contributes to the regulation of mitotic progression, and inhibition of caspases can delay mitotic exit. Additionally, p21(WAF1/CIP1), a CDK inhibitor, can inhibit cell cycle progression but not the G2/M transition following methylmercury exposure, indicating differential regulation of phase transitions under stress. These findings highlight the integration of stress and apoptotic signals with the mitotic cell cycle machinery.
Key Genes Involved in GO:0044772 mitotic cell cycle phase transition
The following genes and proteins are key regulators of the mitotic cell cycle phase transition, as supported by the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CDK1 | Catalytic subunit of the CDK1-cyclin B complex that drives G2/M transition | Target for CDK inhibitors; essential for mitotic entry |
| CCNB1 | Regulatory subunit of CDK1; forms maturation promoting factor (MPF) | Overexpression accelerates G2/M; knockdown delays mitosis |
| CCNA2 | Activates CDK2 at S/G2 and CDK1 at G2/M; localizes to cytoplasm to activate PLK1 | Regulates S/G2 transition and PLK1 activation |
| CDC25C | Phosphatase that activates CDK1 by removing inhibitory phosphate | Phosphorylated by AMPK in metabolic checkpoint |
| PLK1 | Kinase that activates CDC25C and promotes mitotic entry | Target for cancer therapy; regulates G2/M transition |
| APC/C | Ubiquitin ligase that triggers metaphase-to-anaphase transition by degrading securin and cyclin B | Controls mitotic exit; defects cause aneuploidy |
| Securin | Inhibits separase; degraded by APC/C to allow sister chromatid separation | Key substrate for metaphase-to-anaphase transition |
| Separase | Protease that cleaves cohesin to separate sister chromatids | Activated at anaphase onset; essential for chromosome segregation |
| Condensin | Protein complex that compacts mitotic chromosomes | Influences chromatin material properties during phase transition |
| Topoisomerase II | Enzyme that resolves DNA catenanes during mitosis | Required for chromosome condensation and segregation |
| p21(WAF1/CIP1) | CDK inhibitor that modulates cell cycle progression under stress | Inhibits progression but not G2/M after methylmercury |
| Caspase-3 | Apoptotic protease that can also regulate mitotic phase transitions | Contributes to cell cycle regulation at mitotic phase |
| AMPK | Energy sensor that phosphorylates CDC25C to delay G2/M under low energy | Mediates metabolic checkpoint at G2/M |
| RB | Retinoblastoma protein; phosphorylated by CDK2-cyclin E to release E2F at G1/S | Gatekeeper of G1/S transition |
| E2F | Transcription factor that activates S-phase genes upon RB phosphorylation | Drives G1/S transition |
| Cln3 | G1 cyclin in Saccharomyces cerevisiae that activates Cdc28 at G1/S | Model for G1/S transition studies |
| Cdc28 | CDK in budding yeast that controls G1/S and G2/M transitions | Conserved regulator of phase transitions |
| Swi4/Swi6 | Transcription factors that regulate G1/S genes in yeast | Downstream of Cln3-Cdc28 at G1/S |
How Is mitotic cell cycle phase transition Regulated?
The mitotic cell cycle phase transition is regulated by a complex network of kinases, phosphatases, and checkpoints. CDK1-cyclin B activity is controlled by phosphorylation and dephosphorylation events: Wee1 kinase adds inhibitory phosphates, while CDC25C removes them. PLK1 further activates CDC25C, creating a positive feedback loop that ensures switch-like activation. The AMPK metabolic checkpoint can phosphorylate CDC25C, delaying G2/M under low energy conditions. The spindle assembly checkpoint (SAC) monitors kinetochore attachments and inhibits APC/C until all chromosomes are properly aligned, thereby regulating the metaphase-to-anaphase transition. In budding yeast, the mitotic exit network (MEN) coordinates exit from mitosis with cytokinesis. Additionally, caspases and p21(WAF1/CIP1) can modulate phase transitions under stress conditions. These regulatory mechanisms ensure that phase transitions occur only when conditions are favorable and that errors are corrected before progression.
mitotic cell cycle phase transition and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CCNB1 | Lung adenocarcinoma; poor prognosis | Knockout in A549 cells; overexpression in BEAS-2B |
| CDC25C | Metabolic stress response; cancer | Point mutation (S216A) knock-in in HeLa cells |
| PLK1 | Cancer; mitotic entry | Knockout in HCT116; inhibitor treatment |
| APC/C | Aneuploidy; cancer | Knockout of APC subunits in RPE1 cells |
| p21(WAF1/CIP1) | Stress-induced cell cycle arrest | Knockout in HFF cells; methylmercury exposure |
Cancer and Mitotic Phase Transitions
Deregulation of mitotic cell cycle phase transitions is a hallmark of cancer. Overexpression of cyclins and CDKs, or loss of checkpoint control, leads to uncontrolled proliferation and genomic instability. A mitotic cell cycle-associated nomogram based on gene expression predicts overall survival in lung adenocarcinoma, underscoring the clinical relevance of these genes. Targeting CDKs, PLK1, and other regulators has emerged as a therapeutic strategy, with several inhibitors in clinical trials.
Aneuploidy and Chromosomal Instability
Defects in the metaphase-to-anaphase transition, such as weakened spindle assembly checkpoint, cause chromosome mis-segregation and aneuploidy, which can promote tumorigenesis. The material properties of mitotic chromosomes also influence segregation fidelity; altered phase transitions may lead to chromosome breakage or perforation by microtubules. These defects are associated with cancer and developmental disorders.
Metabolic Stress and Cell Cycle Checkpoints
The AMPK-mediated phosphorylation of CDC25C links metabolic stress to the G2/M transition, allowing cells to delay division under low energy conditions. This metabolic checkpoint is important in diseases such as diabetes and cancer, where energy homeostasis is disrupted. Additionally, p21(WAF1/CIP1) modulates cell cycle progression following exposure to toxins like methylmercury, affecting cell fate decisions.
Caspase Crosstalk in Disease
Caspases, beyond their apoptotic roles, can regulate mitotic phase transitions, and their dysregulation may contribute to diseases characterized by aberrant cell cycle and apoptosis, such as cancer and neurodegeneration. Understanding this crosstalk may reveal new therapeutic targets.
From mitotic cell cycle phase transition-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate G2/M transition? | CRISPR knockout in HeLa cells followed by flow cytometry |
| Does point mutation in CDC25C affect AMPK phosphorylation? | Knock-in of S216A mutation in HeLa cells |
| Does overexpression of cyclin A2 alter PLK1 activation? | Overexpression of CCNA2 in U2OS cells |
| Does caspase inhibition delay mitotic exit? | Knockout of caspase-3 in MCF-7 cells |
| Does p21 loss affect G2/M after stress? | p21 knockout in HCT116 cells treated with methylmercury |
| Does condensin mutation alter chromatin phase transition? | Point mutations in condensin subunits in yeast |
How to Study the mitotic cell cycle phase transition Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Flow cytometry | DNA content and phospho-histone H3 | Quantify G1/S and G2/M transitions |
| Live-cell imaging | Dynamics of fluorescently tagged proteins | Track mitotic entry and exit |
| Phosphoproteomics | Global phosphorylation changes | Identify signaling events at phase transitions |
| RNA-seq | Transcriptomic profiles | Discover gene expression signatures |
| CRISPR screen | Gene essentiality | Identify regulators of phase transitions |
| Western blot | Protein expression and phosphorylation | Validate CDK1 activity and CDC25C phosphorylation |
| Immunofluorescence | Subcellular localization | Assess cyclin A2 localization at S/G2 |
| Yeast genetics | Genetic interactions | Study conserved phase transition mechanisms |
Flow Cytometry and Live-Cell Imaging
Flow cytometry using DNA dyes (e.g., propidium iodide) and phospho-histone H3 antibodies allows quantification of cells in different cell cycle phases, enabling assessment of phase transitions. Live-cell imaging with fluorescently tagged proteins (e.g., GFP-cyclin B) tracks the dynamics of transition commitment in real time.
Phosphoproteomics
Mass spectrometry-based phosphoproteomics identifies phosphorylation events on CDKs, CDC25C, and other regulators during phase transitions, revealing signaling networks. This method can uncover novel substrates and crosstalk.
Transcriptomic Profiling and Nomograms
RNA sequencing of synchronized cell populations or patient samples identifies gene expression signatures associated with phase transitions. A mitotic cell cycle-associated nomogram was developed to predict overall survival in lung adenocarcinoma using such data.
CRISPR Screens
Genome-wide CRISPR knockout screens can identify genes essential for specific phase transitions. For example, screens for resistance to CDK inhibitors or spindle poisons reveal regulators of G2/M and metaphase-to-anaphase transitions.
How CRISPR Can Be Used to Study GO:0044772 mitotic cell cycle phase transition
Knockout
CRISPR knockout of genes such as CDK1, CCNB1, or PLK1 in cell lines (e.g., HeLa, HCT116) can abolish specific phase transitions, leading to cell cycle arrest. These models are used to validate gene essentiality and to study checkpoint adaptation.
Point Mutation
Knock-in of point mutations, such as CDC25C S216A to prevent AMPK phosphorylation, allows dissection of specific regulatory phosphorylation sites. This approach reveals how metabolic checkpoints control G2/M transition.
Knock-in
Tagged knock-in of genes like CCNA2 with fluorescent proteins (e.g., GFP) enables live-cell imaging of protein localization and dynamics during phase transitions. Knock-in of degron tags allows rapid depletion to study acute effects.
Overexpression
Overexpression of cyclins or CDKs (e.g., CCNB1, CCNA2) accelerates phase transitions and can transform cells, providing models for cancer research and drug testing.
How EDITGENE Supports mitotic cell cycle phase transition Research
Researchers studying mitotic cell cycle phase transition-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated with it. CRISPR-based models provide the gold standard for establishing causality, and EDITGENE offers a comprehensive suite of services to generate such models efficiently.
Contact EDITGENE today to design your custom CRISPR model for mitotic cell cycle phase transition research.
Frequently Asked Questions About mitotic cell cycle phase transition
What is GO:0044772?
GO:0044772 is the Gene Ontology term for mitotic cell cycle phase transition, defined as the cell cycle process by which a cell commits to entering the next mitotic cell cycle phase.
What genes are involved in mitotic cell cycle phase transition?
Key genes include CDK1, CCNB1, CCNA2, CDC25C, PLK1, APC/C subunits, and checkpoint kinases such as AMPK.
How is the G2/M transition regulated?
The G2/M transition is regulated by CDK1-cyclin B activation, which is controlled by CDC25C and PLK1, and can be delayed by AMPK-mediated phosphorylation of CDC25C.
What is the role of PLK1 in phase transitions?
PLK1 activates CDC25C and promotes mitotic entry, and its localization is regulated by cyclin A2 at the S/G2 transition.
How does the spindle assembly checkpoint control the metaphase-to-anaphase transition?
The spindle assembly checkpoint inhibits APC/C until all chromosomes are properly attached, preventing premature sister chromatid separation.
What diseases are associated with defects in mitotic phase transitions?
Defects are associated with cancer, aneuploidy, and genomic instability; mitotic gene expression predicts survival in lung adenocarcinoma.
Can caspases regulate the mitotic cell cycle?
Yes, caspases can modulate cell cycle regulation at mitotic phases, revealing crosstalk between apoptosis and cell cycle machinery.
How does p21 affect mitotic phase transitions?
p21(WAF1/CIP1) inhibits cell cycle progression but not G2/M transition following methylmercury exposure, indicating differential regulation.
What is the material phase transition of mitotic chromosomes?
It is a change in the physical properties of mitotic chromatin that prevents perforation by microtubules, involving condensins and topoisomerase II.
What experimental models are used to study mitotic phase transitions?
Common models include CRISPR knockout/knock-in cell lines, live-cell imaging, phosphoproteomics, and yeast genetics.
Conclusion
GO:0044772 (mitotic cell cycle phase transition) is a central biological process that ensures faithful progression through the cell cycle. Its regulation by CDKs, cyclins, phosphatases, and checkpoints is critical for genomic stability, and its dysregulation drives cancer and other proliferative disorders. Recent advances have also revealed biophysical aspects, such as the material phase transition of mitotic chromosomes, adding new layers of complexity. Researchers can leverage CRISPR-based models and multi-omics approaches to dissect the mechanisms and identify therapeutic targets. EDITGENE provides comprehensive services to support such studies, from knockout and knock-in cell lines to library screening and bioinformatics.
References
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- 2. He X et al.. 2023. The mitotic cell cycle-associated nomogram predicts overall survival in lung adenocarcinoma.. Cancer Med 12(23):21519-21530 PMID: 37930238
- 3. Matellán L et al.. 2020. Regulation of Mitotic Exit by Cell Cycle Checkpoints: Lessons From Saccharomyces cerevisiae.. Genes (Basel) 11(2) PMID: 32059558
- 4. Hashimoto T et al.. 2011. Contribution of caspase(s) to the cell cycle regulation at mitotic phase.. PLoS One 6(3):e18449 PMID: 21479177
- 5. Mendoza MA et al.. 2002. p21(WAF1/CIP1) inhibits cell cycle progression but not G2/M-phase transition following methylmercury exposure.. Toxicol Appl Pharmacol 178(2):117-25 PMID: 11814332
- 6. Silva Cascales H et al.. 2021. Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1.. Life Sci Alliance 4(3) PMID: 33402344
- 7. Shen Y et al.. 2018. Phosphorylation of CDC25C by AMP-activated protein kinase mediates a metabolic checkpoint during cell-cycle G(2)/M-phase transition.. J Biol Chem 293(14):5185-5199 PMID: 29467227
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