GO:0062033 positive regulation of mitotic sister chromatid segregation: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0062033 describes any process that starts or increases the frequency, rate or extent of sister chromatid segregation during mitosis.
• Positive regulators include cohesin, condensin, separase, Cdk1-cyclin B1, USP37, Wapl, Naa50/NatA and topoisomerase 2a [2,4,5,6,7,8].
• Condensin promotes mitotic chromosome architecture and centromere organization required for sister chromatid segregation.
• Separase is positively regulated by Cdk1-cyclin B1 phosphorylation, explaining why securin is dispensable in vertebrates.
• USP37 deubiquitinase regulates chromosome cohesion and mitotic progression, acting as a positive regulator.
• Dysregulation of these processes is linked to cancer, genome instability and developmental defects [3,7].
Description
Positive regulation of mitotic sister chromatid segregation (GO:0062033) is a biological process that ensures the faithful separation of duplicated chromosomes during mitosis. This process is essential for maintaining genomic integrity and preventing aneuploidy, a hallmark of cancer and developmental disorders. The term encompasses molecular events that initiate or enhance the frequency, rate or extent of sister chromatid segregation, including the action of cohesin, condensin, separase, and cell cycle kinases [2,5,8]. Understanding the positive regulators of sister chromatid segregation is critical for researchers studying cell division, chromosome biology, and cancer therapeutics [3,7]. This article integrates authoritative QuickGO data with verified PubMed literature to provide a comprehensive overview of the mechanisms, key genes, and experimental models for studying GO:0062033.
positive regulation of mitotic sister chromatid segregation At A Glance
| GO ID | GO:0062033 |
|---|---|
| GO term | positive regulation of mitotic sister chromatid segregation |
| Ontology | biological_process |
| Synonym | none |
| Major function | Starts or increases the frequency, rate or extent of sister chromatid segregation during mitosis |
| Related processes | Mitotic sister chromatid segregation, chromosome cohesion, condensin function, separase activation |
| Key regulators | Condensin, cohesin, separase, Cdk1-cyclin B1, USP37, Wapl, Naa50/NatA, topoisomerase 2a |
| Disease relevance | Cancer, genome instability, developmental disorders |
What Is GO:0062033?
GO:0062033 is defined as any process that starts or increases the frequency, rate or extent of sister chromatid segregation during mitosis. In other words, it covers the positive regulatory inputs that promote the timely and accurate separation of sister chromatids, as opposed to the core segregation machinery itself.
Why Is positive regulation of mitotic sister chromatid segregation Important in Cell Biology?
Positive regulation of mitotic sister chromatid segregation is fundamental for genome stability. Errors in this process lead to aneuploidy, which is a common feature of cancer and congenital disorders [1,3]. The identification of positive regulators such as condensin, separase, and USP37 has provided mechanistic insights into how cells ensure accurate chromosome segregation [2,5,6]. Moreover, these regulators are potential therapeutic targets, as their dysregulation contributes to tumorigenesis and chemoresistance.
• Ensures faithful chromosome segregation and prevents aneuploidy.
• Condensin promotes mitotic chromosome architecture and centromere organization.
• Separase activation by Cdk1-cyclin B1 is a key positive regulatory step.
• USP37 deubiquitinase regulates chromosome cohesion and mitotic progression.
• Wapl is a cohesin inhibitor whose structure informs regulatory mechanisms.
• Naa50 and NatA have opposing functions in sister-chromatid cohesion.
• Topoisomerase 2a-dependent G2 arrest requires p53 in cancer cells.
• CENP-A assembly and inheritance are cell cycle controlled.
• Dysregulation leads to cancer, genome instability, and developmental defects [1,3,7].
• Targeting positive regulators may offer therapeutic strategies in oncology.
What Happens During positive regulation of mitotic sister chromatid segregation?
Condensin-mediated chromosome architecture
In simple terms: Condensin helps package chromosomes into compact structures so they can be separated properly.
Condensin is a positive regulator of mitotic sister chromatid segregation. In C. elegans, condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis. Loss of condensin function leads to defects in chromosome segregation, highlighting its essential role.
Separase activation by Cdk1-cyclin B1
In simple terms: A kinase called Cdk1-cyclin B1 activates separase, the enzyme that cuts the rings holding sister chromatids together.
Separase is a protease that cleaves cohesin to allow sister chromatid separation. In vertebrates, Cdk1-cyclin B1 positively regulates separase by phosphorylation, and this regulation may explain why securin is dispensable for separase activation. This positive regulation ensures timely segregation.
USP37 deubiquitinase and cohesion
In simple terms: USP37 removes ubiquitin tags from proteins, which helps maintain chromosome cohesion and allows mitosis to proceed.
The deubiquitinase USP37 regulates chromosome cohesion and mitotic progression. Depletion of USP37 leads to cohesion defects and mitotic delays, indicating that it positively regulates sister chromatid segregation.
Naa50 and NatA in sister-chromatid cohesion
In simple terms: Two acetyltransferases, Naa50 and NatA, have opposite effects on holding sister chromatids together.
N-terminal acetyltransferases Naa50 and NatA have opposing functions in sister-chromatid cohesion. Naa50 promotes cohesion, while NatA antagonizes it, thereby contributing to the positive regulation of segregation.
Topoisomerase 2a and G2 arrest
In simple terms: Topoisomerase 2a helps untangle DNA, and when it is inhibited, cells with p53 arrest in G2 to protect the genome.
Topoisomerase 2a-dependent G2 arrest requires p53 in hTERT-positive cancer cells. This checkpoint response is a positive regulatory mechanism that prevents segregation errors when DNA topology is compromised.
Key Genes Involved in GO:0062033 positive regulation of mitotic sister chromatid segregation
The following genes and proteins are key positive regulators of mitotic sister chromatid segregation, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| Condensin | Promotes mitotic chromosome architecture and centromere organization | Essential for sister chromatid segregation; studied in C. elegans |
| Separase | Cleaves cohesin to allow sister chromatid separation | Positively regulated by Cdk1-cyclin B1 |
| Cdk1-cyclin B1 | Phosphorylates separase to activate it | Key positive regulator of separase |
| USP37 | Deubiquitinase that regulates chromosome cohesion | Positively regulates mitotic progression |
| Wapl | Cohesin inhibitor; structure determined | Regulates cohesin dynamics |
| Naa50 | N-terminal acetyltransferase that promotes cohesion | Opposes NatA in sister-chromatid cohesion |
| NatA | N-terminal acetyltransferase that antagonizes cohesion | Opposing function to Naa50 |
| Topoisomerase 2a | Resolves DNA topology; involved in G2 arrest | p53-dependent G2 arrest in cancer cells |
| CENP-A | Centromere-specific histone H3 variant | Cell cycle control of assembly and inheritance |
| Cohesin | Holds sister chromatids together | Cleaved by separase; regulated by Wapl |
| Securin | Separase inhibitor; dispensable in vertebrates | Regulation by Cdk1-cyclin B1 |
| p53 | Tumor suppressor; mediates G2 arrest | Required for topoisomerase 2a-dependent G2 arrest |
| hTERT | Telomerase reverse transcriptase | Context for topoisomerase 2a study |
| Naa50/NatA | Opposing acetyltransferases | Regulate sister-chromatid cohesion |
| Condensin complex | Structural maintenance of chromosomes | Promotes segregation |
| Separase/Cdk1 | Protease/kinase axis | Positive regulation of segregation |
| USP37/cohesin | Deubiquitinase/cohesin axis | Regulates cohesion |
How Is positive regulation of mitotic sister chromatid segregation Regulated?
Positive regulation of mitotic sister chromatid segregation is controlled by cell cycle kinases, phosphatases, and ubiquitin-proteasome systems. Cdk1-cyclin B1 phosphorylates separase to activate it. USP37 deubiquitinates targets to maintain cohesion. Naa50 and NatA provide opposing acetylation signals. Topoisomerase 2a and p53 mediate a G2 checkpoint that prevents segregation errors. CENP-A assembly is cell cycle controlled, ensuring centromere identity.
positive regulation of mitotic sister chromatid segregation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| Topoisomerase 2a | Cancer, G2 arrest | hTERT-positive cancer cell lines with p53 KO |
| Separase | Aneuploidy, cancer | Knockout or point mutant cell lines |
| USP37 | Mitotic defects, cancer | USP37 knockout or overexpression |
| Condensin | Chromosome instability | C. elegans condensin mutants |
| CENP-A | Centromere dysfunction | Cell cycle reporters |
Cancer and genome instability
Dysregulation of positive regulators of sister chromatid segregation leads to aneuploidy, a hallmark of cancer. For example, topoisomerase 2a inhibition triggers p53-dependent G2 arrest in hTERT-positive cancer cells, and loss of this checkpoint may promote tumorigenesis. Condensin and separase defects are associated with chromosome instability [2,5].
Developmental disorders
Mutations in genes controlling chromosome segregation can cause developmental defects. Condensin dysfunction in C. elegans leads to mitotic and meiotic segregation errors. CENP-A inheritance defects may contribute to developmental abnormalities.
Therapeutic targeting
USP37 and separase are potential therapeutic targets because their inhibition affects mitotic progression and cohesion [5,6]. Wapl structure provides a basis for designing inhibitors of cohesin release.
From positive regulation of mitotic sister chromatid segregation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X positively regulate sister chromatid segregation? | Knockout cell line (e.g., CRISPR KO) |
| Does phosphorylation of separase by Cdk1 affect segregation? | Point mutation (phospho-mutant) knock-in |
| Does USP37 deubiquitinase activity require its catalytic cysteine? | Point mutation (catalytic dead) |
| Where does condensin localize during mitosis? | Tagged knock-in (e.g., GFP) |
| Does overexpression of Naa50 rescue cohesion defects? | Overexpression cell line |
| Does p53 mediate G2 arrest upon topoisomerase 2a inhibition? | p53 knockout or knockdown |
How to Study the positive regulation of mitotic sister chromatid segregation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Live-cell imaging | Chromosome segregation dynamics | Assess segregation errors in KO cells |
| Chromosome spreads | Cohesion and aneuploidy | Evaluate cohesion defects |
| Western blot | Protein expression and phosphorylation | Measure separase activation |
| Immunoprecipitation | Protein-protein interactions | Study cohesin complexes |
| CRISPR screen | Gene function in segregation | Identify novel regulators |
| Flow cytometry | Cell cycle profile | Detect G2 arrest |
| RNA-seq | Transcriptional changes | Analyze gene expression upon perturbation |
| Proteomics | Global protein changes | Identify ubiquitination targets of USP37 |
Live-cell imaging
Live-cell imaging of GFP-tagged histones or chromosomes allows real-time visualization of sister chromatid segregation. This method can quantify segregation errors and timing in cells with genetic perturbations.
Chromosome spreads and FISH
Chromosome spreads combined with fluorescence in situ hybridization (FISH) can detect aneuploidy and cohesion defects. This is useful for assessing the impact of positive regulators.
Western blot and immunoprecipitation
Western blotting and immunoprecipitation can measure protein levels, phosphorylation, and interactions of key regulators such as separase, Cdk1, and USP37 [5,6].
CRISPR screening
Genome-wide CRISPR knockout screens can identify novel positive regulators of sister chromatid segregation by selecting for cells with segregation defects or resistance to mitotic poisons.
How CRISPR Can Be Used to Study GO:0062033 positive regulation of mitotic sister chromatid segregation
Knockout
CRISPR knockout of positive regulators such as separase, USP37, or condensin subunits can reveal their essential roles in sister chromatid segregation. For example, USP37 knockout leads to cohesion defects and mitotic delays.
Point Mutation
Point mutations can be introduced to study specific phosphorylation or catalytic sites. For instance, mutating the catalytic cysteine of USP37 or the Cdk1 phosphorylation sites on separase can test their functional importance [5,6].
Knock-in
Knock-in of tagged versions (e.g., GFP, HaloTag) allows visualization and biochemical purification of proteins like condensin or CENP-A to study their dynamics [2,3].
Overexpression
Overexpression of Naa50 or other regulators can rescue or exacerbate cohesion defects, helping to establish sufficiency.
How EDITGENE Supports positive regulation of mitotic sister chromatid segregation Research
Researchers studying positive regulation of mitotic sister chromatid segregation-related genes often need to determine whether a candidate gene is causally involved in this process. EDITGENE provides comprehensive CRISPR services to generate precisely engineered cell models for such investigations.
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Frequently Asked Questions About positive regulation of mitotic sister chromatid segregation
What is GO:0062033?
GO:0062033 is the Gene Ontology term for positive regulation of mitotic sister chromatid segregation, describing processes that start or increase the frequency, rate or extent of sister chromatid separation during mitosis.
What genes are involved in positive regulation of mitotic sister chromatid segregation?
Key genes include condensin, separase, Cdk1-cyclin B1, USP37, Wapl, Naa50, NatA, and topoisomerase 2a [2,4,5,6,7,8].
How does condensin regulate sister chromatid segregation?
Condensin promotes mitotic chromosome architecture and centromere organization, facilitating proper segregation.
What is the role of separase in mitosis?
Separase cleaves cohesin to allow sister chromatid separation and is positively regulated by Cdk1-cyclin B1 phosphorylation.
How does USP37 regulate chromosome cohesion?
USP37 is a deubiquitinase that maintains chromosome cohesion and promotes mitotic progression.
What is the function of Wapl in sister chromatid segregation?
Wapl is a cohesin inhibitor; its structure provides insights into cohesin release regulation.
How do Naa50 and NatA affect sister-chromatid cohesion?
Naa50 and NatA have opposing functions in sister-chromatid cohesion, with Naa50 promoting and NatA antagonizing cohesion.
What is the link between topoisomerase 2a and G2 arrest?
Topoisomerase 2a inhibition triggers p53-dependent G2 arrest in hTERT-positive cancer cells, preventing segregation errors.
How is CENP-A assembly regulated during the cell cycle?
CENP-A assembly and inheritance are cell cycle controlled, ensuring centromere identity for proper segregation.
What experimental models are used to study positive regulation of mitotic sister chromatid segregation?
Common models include CRISPR knockout, point mutation, knock-in, and overexpression cell lines, as well as C. elegans mutants [2,4,5,6,7].
Conclusion
Positive regulation of mitotic sister chromatid segregation (GO:0062033) is a critical biological process that safeguards genome stability. Key positive regulators such as condensin, separase, USP37, and Cdk1-cyclin B1 orchestrate the timely separation of sister chromatids [2,5,6]. Dysregulation of these factors contributes to cancer and developmental disorders, making them attractive therapeutic targets [3,7]. Advanced CRISPR models and screening approaches will continue to uncover new regulatory mechanisms and translational opportunities.
References
- 1. Allshire R. 2001. Dissecting Fission Yeast Centromeres via Silencing.. PMID: 21413369
- 2. Hagstrom KA et al.. 2002. C. elegans condensin promotes mitotic chromosome architecture, centromere organization, and sister chromatid segregation during mitosis and meiosis.. Genes Dev 16(6):729-42 PMID: 11914278
- 3. Rowley G et al.. 2025. A brief historical perspective on cell cycle control of CENP-A assembly and inheritance.. Chromosome Res 33(1):15 PMID: 40715876
- 4. Rong Z et al.. 2016. Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion.. J Biol Chem 291(36):19079-91 PMID: 27422821
- 5. Hellmuth S et al.. 2015. Positive and negative regulation of vertebrate separase by Cdk1-cyclin B1 may explain why securin is dispensable.. J Biol Chem 290(12):8002-10 PMID: 25659430
- 6. Yeh C et al.. 2015. The Deubiquitinase USP37 Regulates Chromosome Cohesion and Mitotic Progression.. Curr Biol 25(17):2290-9 PMID: 26299517
- 7. Lockwood N et al.. 2022. Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells.. Cancer Res 82(9):1762-1773 PMID: 35247890
- 8. Ouyang Z et al.. 2013. Structure of the human cohesin inhibitor Wapl.. Proc Natl Acad Sci U S A 110(28):11355-60 PMID: 23776203
