GO:2000719 negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric: Regulation, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:2000719 describes any process that stops, prevents, or reduces the maintenance of mitotic sister chromatid cohesion specifically at the centromeric region.
• Centromeric cohesion is essential for accurate chromosome segregation; its negative regulation ensures timely sister chromatid separation during mitosis.
• Naa50/San-dependent N-terminal acetylation of Scc1 (a cohesin subunit) is potentially important for sister chromatid cohesion, linking acetylation to cohesion regulation.
• Defects in cohesion regulation can lead to aneuploidy, a hallmark of cancer and developmental disorders.
• Research tools include CRISPR knockout, point mutation, knock-in, and overexpression models to dissect gene function in cohesion maintenance.
• Understanding GO:2000719 aids in identifying therapeutic targets for diseases linked to chromosome instability.
Description
GO:2000719, negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric, is a biological process that counteracts the persistence of cohesion between sister chromatids at the centromere during mitosis. This regulation is critical for proper chromosome segregation, as centromeric cohesion must be maintained until anaphase and then promptly removed to allow sister chromatid separation. Disruption of this balance can result in aneuploidy, a condition associated with cancer and genetic disorders. Researchers study this process to understand how cells ensure genomic stability and to identify potential therapeutic targets.
negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric At A Glance
| GO ID | GO:2000719 |
|---|---|
| GO term | negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric |
| Ontology | biological_process |
| Synonym | negative regulation of maintenance of centromeric mitotic sister chromatin cohesion; negative regulation of maintenance of mitotic sister chromatin cohesion at centromere; negative regulation of maintenance of sister chromatin cohesion at centromere at mitosis |
| Major function | Counteracts centromeric cohesion to permit sister chromatid separation during mitosis |
| Related cellular component | Centromere, kinetochore, cohesin complex |
| Related molecular function | Protein binding, acetyltransferase activity (e.g., Naa50/San) |
| Key regulator example | Naa50/San-dependent N-terminal acetylation of Scc1 |
What Is GO:2000719?
According to the Gene Ontology, GO:2000719 encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of maintenance of mitotic sister chromatid cohesion in the centromeric region. In other words, it is the negative regulation of the mechanisms that keep sister chromatids attached at their centromeres during mitosis. This process is essential for the timely separation of chromosomes and is tightly regulated by various proteins and modifications.
Why Is negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric Important in Cell Biology?
Proper regulation of centromeric cohesion is fundamental for genomic stability. GO:2000719 ensures that sister chromatids remain attached until the appropriate time and then separate accurately, preventing aneuploidy. Dysregulation of this process is implicated in cancer, where chromosomal instability drives tumor progression, and in developmental disorders characterized by chromosome missegregation. Studying this term helps elucidate the molecular mechanisms of chromosome segregation and identifies targets for therapeutic intervention.
• Prevents premature sister chromatid separation, which can cause aneuploidy.
• Ensures accurate chromosome segregation during mitosis.
• Its dysregulation is linked to cancer and chromosomal instability.
• Involves post-translational modifications such as N-terminal acetylation of Scc1.
• Provides targets for cancer therapy aimed at inducing chromosome instability.
• Relevant to understanding developmental disorders with cohesion defects.
• Helps explain mechanisms of drug resistance in cancer cells.
• Aids in the development of CRISPR-based models for studying cohesion.
What Happens During negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric?
Initiation of Cohesion Removal
In simple terms: The cell starts to loosen the glue holding sister chromatids together at the centromere.
Negative regulation of centromeric cohesion is initiated by specific signals that trigger the removal or inactivation of cohesin complexes at the centromere. This process involves the action of separase, which cleaves the cohesin subunit Scc1, leading to loss of cohesion. However, the exact triggers and regulatory pathways are still being elucidated.
Role of N-terminal Acetylation
In simple terms: A chemical tag added to a protein helps control when cohesion is removed.
Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion. This modification may influence the stability or interactions of Scc1, thereby affecting the maintenance of cohesion and its negative regulation. The precise mechanism by which acetylation impacts cohesion dynamics remains an active area of research.
Chromosome Segregation and Aneuploidy
In simple terms: When cohesion is not properly removed, chromosomes can be mis-segregated, leading to cells with abnormal chromosome numbers.
Failure to negatively regulate centromeric cohesion can result in aneuploidy, a hallmark of cancer and developmental disorders. Proper timing of cohesion removal is essential for bipolar spindle attachment and accurate chromosome segregation. Studies in model organisms have shown that defects in this process lead to random chromosome distribution and meiotic errors.
Meiotic Implications
In simple terms: Similar cohesion regulation occurs in meiosis, and errors can cause infertility or miscarriage.
Although GO:2000719 is specific to mitosis, related processes in meiosis are crucial for gamete formation. Disomic substitution lines in rye hybrids exhibit random chromosome distribution without bipolar spindle assembly, highlighting the importance of cohesion regulation in meiosis. Understanding mitotic regulation can inform studies of meiotic cohesion and its impact on fertility.
Key Genes Involved in GO:2000719 negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric
The following genes and proteins are key players in the negative regulation of centromeric cohesion, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SCC1 | Cohesin subunit; cleaved by separase to remove cohesion | N-terminal acetylation by Naa50/San affects cohesion |
| NAA50 | N-terminal acetyltransferase; acetylates Scc1 | Potential regulator of cohesion maintenance |
| SAN | N-terminal acetyltransferase; acetylates Scc1 | Potential regulator of cohesion maintenance |
| SEPARASE | Protease that cleaves Scc1 | Executes cohesion removal |
| SCC2 | Cohesin loading factor | Required for cohesion establishment |
| SCC4 | Cohesin loading factor | Required for cohesion establishment |
| SMC1 | Cohesin subunit | Structural component of cohesin |
| SMC3 | Cohesin subunit | Structural component of cohesin |
| SCC3 | Cohesin subunit | Regulatory subunit of cohesin |
| PDS5 | Cohesin-associated protein | Regulates cohesion dynamics |
| WAPL | Cohesin release factor | Promotes cohesion removal |
| PLK1 | Mitotic kinase | Phosphorylates cohesin subunits |
| AURORA B | Mitotic kinase | Regulates chromosome segregation |
| BUB1 | Spindle checkpoint kinase | Monitors chromosome attachment |
| MAD2 | Spindle checkpoint protein | Inhibits anaphase until chromosomes are aligned |
| CDC20 | Activator of anaphase-promoting complex | Triggers separase activation |
| APC/C | Ubiquitin ligase | Targets securin for degradation |
| SECURIN | Inhibitor of separase | Regulates separase activity |
How Is negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric Regulated?
The negative regulation of centromeric cohesion is controlled by a network of kinases and phosphatases that modulate the activity of cohesin and its regulators. For example, phosphorylation of cohesin subunits by Plk1 and Aurora B can influence cohesion stability. Additionally, N-terminal acetylation of Scc1 by Naa50/San may serve as a regulatory mark. The spindle assembly checkpoint ensures that cohesion is not removed until all chromosomes are properly attached to the spindle.
negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SCC1 | Cancer, cohesinopathy | Knockout in cancer cell lines |
| NAA50 | Cancer, developmental disorders | Point mutation in HEK293 |
| SEPARASE | Cancer, aneuploidy | Overexpression in HeLa |
| WAPL | Cancer, chromosomal instability | Knockout in HCT116 |
| PDS5 | Developmental disorders | Knock-in in iPSCs |
Cancer and Chromosomal Instability
Dysregulation of centromeric cohesion leads to aneuploidy, a common feature of many cancers. Overexpression of cohesin release factors or mutations in cohesin subunits can cause premature sister chromatid separation, contributing to tumorigenesis. Targeting the negative regulation of cohesion may offer therapeutic strategies for cancers with chromosomal instability.
Developmental Disorders
Mutations in cohesin complex genes cause developmental disorders known as cohesinopathies, such as Cornelia de Lange syndrome. While these typically involve loss of cohesion, improper negative regulation could also contribute to developmental defects. Understanding GO:2000719 may shed light on the molecular basis of these disorders.
Infertility and Meiotic Errors
Errors in cohesion regulation during meiosis can lead to infertility, miscarriages, and birth defects. Studies in rye hybrids show that random chromosome distribution without bipolar spindle assembly can result from cohesion defects. Thus, insights into mitotic regulation may inform reproductive biology.
From negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does Naa50 acetylation of Scc1 regulate cohesion? | Point mutation of Scc1 acetylation sites |
| What is the effect of Scc1 cleavage on aneuploidy? | Knockout of separase in cancer cells |
| Can overexpression of WAPL induce chromosomal instability? | Overexpression of WAPL in HeLa |
| How does Naa50 loss affect cell cycle? | Knockout of NAA50 in HEK293 |
| Does a disease-associated mutation in SCC1 affect cohesion? | Knock-in of mutant SCC1 in iPSCs |
| What proteins interact with Scc1 during mitosis? | Tagged knock-in of SCC1 for proteomics |
How to Study the negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Chromosome spreads + FISH | Sister chromatid cohesion at centromeres | Assess cohesion defects |
| Live-cell imaging | Dynamics of cohesin removal | Monitor mitosis in real time |
| Mass spectrometry | Post-translational modifications of cohesin | Identify acetylation sites |
| CRISPR knockout screen | Genes affecting chromosome segregation | Discover novel regulators |
| RNA-seq | Transcriptional changes upon cohesion perturbation | Identify pathways affected |
| Proximity ligation assay | Protein-protein interactions | Detect cohesin interactions |
| Flow cytometry | Cell cycle profile and aneuploidy | Quantify chromosome missegregation |
| Western blot | Protein expression and cleavage | Assess separase activity |
Chromosome Spreads and FISH
Chromosome spreads combined with fluorescence in situ hybridization (FISH) can visualize sister chromatid cohesion at centromeres. This method allows assessment of cohesion defects in cells with perturbations in GO:2000719-related genes.
Live-Cell Imaging
Live-cell imaging of cells expressing fluorescently tagged cohesin subunits or centromere markers enables real-time monitoring of cohesion dynamics. This approach can reveal the timing of cohesion removal during mitosis.
Proteomics and Acetylation Analysis
Mass spectrometry-based proteomics can identify post-translational modifications on cohesin subunits, such as N-terminal acetylation of Scc1. This helps elucidate the regulatory mechanisms of cohesion.
CRISPR Screening
Genome-wide CRISPR knockout screens can identify genes that, when lost, affect centromeric cohesion and chromosome segregation. Such screens are powerful for discovering novel regulators of GO:2000719.
How CRISPR Can Be Used to Study GO:2000719 negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric
Knockout
CRISPR knockout of genes involved in centromeric cohesion, such as SCC1 or NAA50, can reveal their essential roles in mitosis and cell viability. Knockout cell lines are valuable for studying the consequences of losing negative regulation.
Point Mutation
Introducing point mutations in cohesin subunits, such as acetylation site mutants of Scc1, allows precise dissection of regulatory modifications. These models help determine the functional significance of specific residues.
Knock-in
Knock-in of tagged versions of cohesin subunits (e.g., GFP-Scc1) enables live-cell imaging and proteomic studies. Disease-associated mutations can also be knocked in to model cohesinopathies.
Overexpression
Overexpression of cohesin release factors like WAPL can induce premature cohesion loss and aneuploidy. Such models are useful for studying the effects of hyperactive negative regulation.
How EDITGENE Supports negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric Research
Researchers studying negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric-related genes often need to determine whether a candidate gene is causally involved in cohesion dynamics and chromosome segregation. EDITGENE provides comprehensive CRISPR services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric research.
Frequently Asked Questions About negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric
What is GO:2000719?
GO:2000719 is a Gene Ontology term for the biological process that negatively regulates the maintenance of mitotic sister chromatid cohesion specifically at the centromere.
What genes are involved in negative regulation of centromeric cohesion?
Key genes include SCC1, NAA50, SAN, SEPARASE, WAPL, and PDS5, among others.
How does Naa50 regulate sister chromatid cohesion?
Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion, though the exact mechanism is still under study.
Why is centromeric cohesion important?
It ensures that sister chromatids stay together until anaphase, preventing aneuploidy and maintaining genomic stability.
What diseases are linked to defects in cohesion regulation?
Cancer, developmental disorders like Cornelia de Lange syndrome, and infertility have been associated with cohesion defects.
What methods are used to study centromeric cohesion?
Common methods include chromosome spreads, live-cell imaging, proteomics, and CRISPR screens.
Can CRISPR be used to study GO:2000719?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are powerful tools to dissect the regulation of centromeric cohesion.
What is the role of separase in cohesion removal?
Separase cleaves the cohesin subunit Scc1, leading to loss of cohesion and allowing sister chromatid separation.
How does aneuploidy arise from cohesion defects?
Premature or failed cohesion removal can cause chromosomes to mis-segregate, resulting in daughter cells with abnormal chromosome numbers.
What model organisms are used to study cohesion?
Yeast, Drosophila, and mammalian cell lines are commonly used, and studies in rye hybrids have also provided insights.
Conclusion
GO:2000719, negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric, is a critical process for genomic stability. Its dysregulation leads to aneuploidy and diseases such as cancer. Ongoing research, aided by CRISPR technologies, continues to unravel the molecular players and regulatory mechanisms, offering potential therapeutic avenues.
References
- 1. Ribeiro AL et al.. 2016. Naa50/San-dependent N-terminal acetylation of Scc1 is potentially important for sister chromatid cohesion.. Sci Rep 6:39118 PMID: 27996020
- 2. Loginova DB et al.. 2020. Random chromosome distribution in the first meiosis of F1 disomic substitution line 2R(2D) x rye hybrids (ABDR, 4× = 28) occurs without bipolar spindle assembly.. Comp Cytogenet 14(4):453-482 PMID: 33117496
