GO:1902100 negative regulation of metaphase/anaphase transition of cell cycle: Regulation, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902100 describes any process that stops, prevents, or reduces the frequency, rate, or extent of the metaphase-to-anaphase transition.
• This regulatory step ensures faithful chromosome segregation by delaying anaphase until all chromosomes are properly attached to the spindle.
• Key molecular players include cell cycle-regulated proteolysis machinery, SUMO-2/3, topoisomerase II, and CDK1-cyclin B [1,4,5].
• Dysregulation of this transition is linked to cancer, where genes such as FAM64A and CDC6 are aberrantly expressed [6,7,8].
• Research models include knockout, point-mutation, knock-in, and overexpression cell lines to dissect gene function [1,5].
• Understanding this process aids in identifying therapeutic targets for diseases of uncontrolled cell division [6,7].
Description
The metaphase-to-anaphase transition is a critical checkpoint in the cell cycle, ensuring that sister chromatids separate only after all chromosomes are correctly attached to the mitotic spindle. Negative regulation of this transition, annotated as GO:1902100, encompasses processes that delay or inhibit this switch, thereby preventing premature chromosome segregation and maintaining genomic stability. This regulation is essential for normal development and tissue homeostasis, and its disruption can lead to aneuploidy and cancer [6,7]. Researchers study this term to understand the molecular brakes that control cell division, with implications for cancer therapy and regenerative medicine. The process involves a complex interplay of protein phosphorylation, ubiquitin-mediated proteolysis, and sumoylation [1,4,5].
negative regulation of metaphase/anaphase transition of cell cycle At A Glance
| GO ID | GO:1902100 |
|---|---|
| GO term | negative regulation of metaphase/anaphase transition of cell cycle |
| Ontology | biological_process |
| Synonym | down regulation of metaphase/anaphase transition of cell cycle, down-regulation of metaphase/anaphase transition of cell cycle, downregulation of metaphase/anaphase transition of cell cycle, inhibition of metaphase/anaphase transition of cell cycle |
| Major function | Delays or prevents the onset of anaphase to ensure proper chromosome segregation [1,2] |
| Related processes | Spindle assembly checkpoint, ubiquitin-mediated proteolysis, sumoylation [1,4] |
| Key regulators | CDK1, cyclin B, APC/C, SUMO-2/3, topoisomerase II [1,4,5] |
| Disease relevance | Cancer, aneuploidy, developmental disorders [6,7,8] |
What Is GO:1902100?
GO:1902100, negative regulation of metaphase/anaphase transition of cell cycle, refers to any biological process that stops, prevents, or reduces the frequency, rate, or extent of the metaphase-to-anaphase transition. This includes mechanisms that delay anaphase onset in response to unattached kinetochores or other cellular signals, ensuring accurate chromosome segregation.
Why Is negative regulation of metaphase/anaphase transition of cell cycle Important in Cell Biology?
Negative regulation of the metaphase/anaphase transition is vital for genomic integrity; it provides a temporal window for error correction before sister chromatids separate. Failure of this regulation can result in aneuploidy, a hallmark of cancer and congenital disorders [6,7]. Understanding the molecular mechanisms offers opportunities for targeted therapies that exploit checkpoint weaknesses in cancer cells.
• Prevents premature chromosome segregation and aneuploidy.
• Coordinates with the spindle assembly checkpoint to ensure proper attachment.
• Involves ubiquitin-mediated proteolysis of mitotic targets.
• Regulated by phosphorylation and sumoylation [4,5].
• Dysregulation is associated with breast cancer, melanoma, and gynecological cancers [6,7,8].
• Provides targets for chemotherapeutic intervention [6,7].
• Essential for normal development and tissue homeostasis.
• Studied using advanced CRISPR models for gene function [1,5].
What Happens During negative regulation of metaphase/anaphase transition of cell cycle?
Spindle Assembly Checkpoint Activation
In simple terms: The cell has a safety checkpoint that stops division until all chromosomes are properly lined up.
The spindle assembly checkpoint (SAC) monitors kinetochore-microtubule attachments and generates a 'wait' signal that inhibits the anaphase-promoting complex/cyclosome (APC/C), thereby preventing anaphase onset [1,2]. This negative regulation ensures that chromosomes are correctly bi-oriented before segregation.
Inhibition of APC/C by the Mitotic Checkpoint Complex
In simple terms: A protein complex puts a brake on the machinery that would otherwise trigger chromosome separation.
The mitotic checkpoint complex (MCC), composed of Mad2, BubR1, Bub3, and Cdc20, sequesters Cdc20 and inhibits APC/C activity, blocking the ubiquitination and degradation of securin and cyclin B. This inhibition is a key mechanism of negative regulation of the metaphase/anaphase transition.
Phosphorylation-Dependent Regulation of CDK1
In simple terms: Chemical tags on the cell division engine can keep it switched off until the right time.
CDK1-cyclin B kinase activity is required for entry into mitosis, but its downregulation is necessary for anaphase. Phosphorylation site mutants of cdc2p fail to promote the metaphase-to-anaphase transition, indicating that precise phosphorylation control is critical. Negative regulation may involve maintaining CDK1 activity or preventing its premature inactivation.
SUMOylation and Topoisomerase II Regulation
In simple terms: Small proteins can attach to other proteins to change their function during cell division.
SUMO-2/3 conjugation regulates topoisomerase II activity in mitosis, and disruption of this modification affects chromosome segregation. This sumoylation pathway contributes to the negative regulation of the metaphase/anaphase transition by modulating chromatin and spindle dynamics.
Proteolysis of Mitotic Target Proteins
In simple terms: The cell destroys specific proteins at the right time to control the timing of division.
Cell cycle-regulated proteolysis of mitotic target proteins, such as securin and cyclin B, is essential for anaphase onset; negative regulation prevents their premature degradation. This proteolysis is mediated by APC/C and is tightly controlled by the SAC.
Key Genes Involved in GO:1902100 negative regulation of metaphase/anaphase transition of cell cycle
The following genes and proteins are central to the negative regulation of the metaphase/anaphase transition, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CDK1 | Cyclin-dependent kinase 1; drives mitosis and its regulation is critical for transition | Point mutations in CDK1 affect metaphase-to-anaphase progression |
| CCNB1 | Cyclin B1; regulatory subunit of CDK1, degradation needed for anaphase | Proteolysis studies reveal timing of transition |
| APC/C | Anaphase-promoting complex/cyclosome; ubiquitin ligase that targets securin and cyclin B | Inhibition by SAC is key to negative regulation |
| MAD2 | Mitotic arrest deficient 2; component of MCC that inhibits APC/C | Knockdown causes premature anaphase |
| BUBR1 | Bub1-related kinase; part of MCC, ensures checkpoint function | Mutations linked to aneuploidy |
| BUB3 | Budding uninhibited by benzimidazoles 3; MCC component | Required for checkpoint signaling |
| CDC20 | Cell division cycle 20; activator of APC/C, sequestered by MCC | Overexpression can override checkpoint |
| SUMO2 | Small ubiquitin-like modifier 2; regulates topoisomerase II in mitosis | SUMOylation affects chromosome segregation |
| SUMO3 | Small ubiquitin-like modifier 3; similar to SUMO2 | SUMO-2/3 regulates topoisomerase II |
| TOP2A | Topoisomerase II alpha; regulated by SUMOylation during mitosis | Inhibition affects metaphase/anaphase transition |
| FAM64A | Family with sequence similarity 64 member A; involved in proliferation and migration [6,8] | Knockdown suppresses breast cancer cell proliferation |
| CDC6 | Cell division cycle 6; DNA replication licensing factor, aberrantly methylated in melanoma | Potential biomarker and therapeutic target |
| PTTG1 | Securin; inhibits separase, must be degraded for anaphase | Proteolysis is cell cycle-regulated |
| ESPL1 | Separase; cleaves cohesin to allow sister chromatid separation | Inhibited by securin until anaphase |
| PLK1 | Polo-like kinase 1; regulates mitotic progression and checkpoint recovery | Involved in phosphorylation of mitotic targets |
| AURKA | Aurora kinase A; regulates centrosome maturation and spindle assembly | Inhibition affects chromosome alignment |
| AURKB | Aurora kinase B; chromosome passenger complex, regulates kinetochore attachments | Required for checkpoint satisfaction |
| MAD1 | Mitotic arrest deficient 1; MCC component | Mutations impair checkpoint |
How Is negative regulation of metaphase/anaphase transition of cell cycle Regulated?
The negative regulation of the metaphase/anaphase transition is controlled by the spindle assembly checkpoint, which senses unattached kinetochores and inhibits APC/C through the mitotic checkpoint complex. Phosphorylation by CDK1 and other kinases modulates checkpoint components, while SUMOylation regulates topoisomerase II and other mitotic proteins [4,5]. Proteolysis of cyclin B and securin is tightly regulated to ensure timely anaphase onset.
negative regulation of metaphase/anaphase transition of cell cycle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| FAM64A | Breast cancer proliferation and migration | Knockdown in breast cancer cell lines |
| CDC6 | Melanoma, aberrant methylation | Overexpression or knockout in melanoma cells |
| FAM64A | Gynecological cancers, prognostic marker | Expression analysis in patient samples |
| CDK1 | Cell cycle dysregulation in cancer | Point mutation knock-in in cell lines |
| SUMO2/3 | Mitotic defects and cancer | Knockout or knock-in of SUMOylation sites |
Cancer and Aneuploidy
Defects in the negative regulation of the metaphase/anaphase transition lead to chromosomal instability and aneuploidy, which are hallmarks of many cancers [6,7]. For example, FAM64A knockdown suppresses breast cancer cell proliferation and migration, suggesting its role in promoting transition. CDC6 is aberrantly methylated and differentially expressed in melanoma, linking it to cell cycle dysregulation.
Gynecological Cancers
Bioinformatics analysis of FAM64A mRNA expression in gynecological cancers indicates its prognostic significance, highlighting the importance of this transition in cancer progression.
Developmental Disorders
Proper regulation of meiosis, which shares mechanisms with mitosis, is crucial for oocyte maturation; disruption can lead to infertility and developmental abnormalities.
From negative regulation of metaphase/anaphase transition of cell cycle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate the metaphase/anaphase transition? | Knockout cell line (e.g., CRISPR-Cas9) |
| How does a specific phosphorylation affect transition? | Point mutation knock-in (e.g., CDK1 mutant) |
| What is the effect of SUMOylation on topoisomerase II? | Knock-in of SUMOylation site mutants |
| Does overexpression of gene Y accelerate anaphase? | Overexpression cell line |
| Can we visualize protein localization during transition? | Tagged knock-in (e.g., GFP) |
| What is the role of gene Z in cancer proliferation? | Knockdown or knockout in cancer cell lines [6,7] |
How to Study the negative regulation of metaphase/anaphase transition of cell cycle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Live-cell imaging | Timing of metaphase-to-anaphase transition | Visualize checkpoint delay |
| Proteomics | Protein degradation and interactions | Identify APC/C substrates |
| Phosphoproteomics | Phosphorylation changes | Study CDK1 substrates |
| SUMOylation assays | SUMO conjugation | Analyze topoisomerase II regulation |
| CRISPR knockout screening | Gene essentiality for transition | Discover novel regulators |
| RNA-seq | Transcriptional changes | Assess gene expression in cancer |
| Bioinformatics analysis | Methylation and expression correlation | Identify biomarkers like CDC6 |
| Immunofluorescence | Protein localization and chromosome alignment | Assess kinetochore attachments |
Live-Cell Imaging
Live-cell imaging with fluorescently tagged chromosomes and spindle components allows real-time visualization of the metaphase-to-anaphase transition and its delay or inhibition.
Proteomics and Degradation Assays
Proteomic approaches and degradation assays can identify cell cycle-regulated proteolysis of mitotic targets, revealing key substrates of APC/C.
Phosphorylation and SUMOylation Analysis
Phosphoproteomics and SUMOylation assays (e.g., SUMO-2/3 conjugation) help dissect post-translational modifications that regulate the transition [4,5].
CRISPR Screening
Genome-wide CRISPR knockout screens can identify genes whose loss alters the metaphase/anaphase transition, providing unbiased insights into regulatory networks.
How CRISPR Can Be Used to Study GO:1902100 negative regulation of metaphase/anaphase transition of cell cycle
Knockout
CRISPR knockout of genes such as MAD2 or BUBR1 can abrogate the negative regulation, leading to premature anaphase and aneuploidy, thus validating their role in the checkpoint.
Point Mutation
Introducing point mutations (e.g., in CDK1 phosphorylation sites) via CRISPR knock-in allows precise dissection of phosphorylation-dependent regulation of the metaphase/anaphase transition.
Knock-in
Knock-in of tagged versions (e.g., GFP) of genes like TOP2A enables live-cell imaging of their dynamics during the transition and SUMOylation studies.
Overexpression
Overexpression of genes such as FAM64A or CDC20 can override the negative regulation, promoting premature anaphase and proliferation, useful for cancer modeling [6,7].
How EDITGENE Supports negative regulation of metaphase/anaphase transition of cell cycle Research
Researchers studying negative regulation of metaphase/anaphase transition of cell cycle-related genes often need to determine whether a candidate gene is causally involved in the regulation of this critical cell cycle checkpoint. EDITGENE provides comprehensive CRISPR-based services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of metaphase/anaphase transition of cell cycle research.
Frequently Asked Questions About negative regulation of metaphase/anaphase transition of cell cycle
What is GO:1902100?
GO:1902100 is a Gene Ontology term for negative regulation of metaphase/anaphase transition of cell cycle, describing processes that delay or prevent anaphase onset.
What genes are involved in negative regulation of metaphase/anaphase transition?
Key genes include CDK1, CCNB1, APC/C components, MAD2, BUBR1, BUB3, CDC20, SUMO2/3, TOP2A, FAM64A, and CDC6 [1,4,5,6,7].
Why is the metaphase/anaphase transition important?
It ensures accurate chromosome segregation; negative regulation prevents premature separation and aneuploidy.
How is the metaphase/anaphase transition regulated?
It is regulated by the spindle assembly checkpoint, which inhibits APC/C through the mitotic checkpoint complex, and by phosphorylation and SUMOylation [1,4,5].
What diseases are associated with defects in this transition?
Cancer, aneuploidy, and developmental disorders are linked to dysregulation of this transition [6,7,8].
What experimental models are used to study this process?
Knockout, point mutation, knock-in, and overexpression cell lines, as well as live-cell imaging and CRISPR screens [1,5,6].
How does SUMOylation affect the metaphase/anaphase transition?
SUMO-2/3 regulates topoisomerase II in mitosis, affecting chromosome segregation.
What is the role of CDK1 in this transition?
CDK1 phosphorylation is critical; mutants fail to promote metaphase-to-anaphase transition.
Can CRISPR be used to study this transition?
Yes, CRISPR knockout, knock-in, and point mutations are powerful tools to dissect gene function in this process [1,5].
What services does EDITGENE offer for this research?
EDITGENE provides knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services [1,4,5,6,7,8].
Conclusion
Negative regulation of the metaphase/anaphase transition (GO:1902100) is a fundamental cell cycle control mechanism that safeguards genomic stability. Its dysregulation contributes to cancer and other diseases, making it a prime target for therapeutic intervention. Advanced CRISPR models and bioinformatics tools are essential for unraveling its complexities and identifying new drug targets.
References
- 1. Bastians H et al.. 1999. Cell cycle-regulated proteolysis of mitotic target proteins.. Mol Biol Cell 10(11):3927-41 PMID: 10564281
- 2. Earnshaw WC et al.. 1989. Proteins of the inner and outer centromere of mitotic chromosomes.. Genome 31(2):541-52 PMID: 2698830
- 3. Albertini DF. 1992. Regulation of meiotic maturation in the mammalian oocyte: interplay between exogenous cues and the microtubule cytoskeleton.. Bioessays 14(2):97-103 PMID: 1575717
- 4. Azuma Y et al.. 2003. SUMO-2/3 regulates topoisomerase II in mitosis.. J Cell Biol 163(3):477-87 PMID: 14597774
- 5. Gould KL et al.. 1998. A phosphorylation site mutant of Schizosaccharomyces pombe cdc2p fails to promote the metaphase to anaphase transition.. Mol Gen Genet 259(4):437-48 PMID: 9790601
- 6. Yao Z et al.. 2019. Knockdown of FAM64A suppresses proliferation and migration of breast cancer cells.. Breast Cancer 26(6):835-845 PMID: 31264076
- 7. Liao L et al.. 2024. Comprehensive analysis of aberrantly methylated differentially expressed genes and validation of CDC6 in melanoma.. J Cancer Res Clin Oncol 150(7):362 PMID: 39052109
- 8. Zheng HC et al.. 2023. A bioinformatics analysis of the clinicopathological and prognostic significance of FAM64A mRNA expression in gynecological cancers.. J Obstet Gynaecol 43(1):2216280 PMID: 37227120
