GO:1902423 regulation of attachment of mitotic spindle microtubules to kinetochore: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1902423 describes the biological process that modulates the frequency, rate or extent of attachment of spindle microtubules to the kinetochore during mitotic sister chromatid segregation.
• This process is essential for accurate chromosome segregation and is tightly regulated by kinases such as MPS1, Aurora A, Aurora B, and phosphatases including PP1 and PP6 [1,2,4,6].
• Key proteins include NDC80 complex components, CENP-F, TPX2, EB1, and the Nup107-160 nucleoporin complex, which influence kinetochore-microtubule attachment stability and spindle assembly [3,4,7,8].
• Dysregulation of this process leads to aneuploidy, chromosomal instability, and is implicated in cancers and developmental disorders [2,8].
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of gene function in this pathway.
• Understanding GO:1902423 provides insights into mitotic regulation and offers potential targets for anticancer therapies.
Description
The attachment of spindle microtubules to kinetochores is a fundamental step in mitosis, ensuring that each daughter cell receives an accurate complement of chromosomes. The Gene Ontology term GO:1902423, regulation of attachment of mitotic spindle microtubules to kinetochore, encompasses any process that modulates the frequency, rate or extent of this attachment during mitotic sister chromatid segregation. This regulation is critical for maintaining genomic stability, and its disruption is associated with chromosomal instability and diseases such as cancer. Research has identified multiple regulatory layers, including kinases like MPS1 and Aurora A, phosphatases such as PP1 and PP6, and structural components like the NDC80 complex and CENP-F [1,4,6,8]. These factors coordinate the dynamic interactions between microtubules and kinetochores to ensure proper bipolar attachment and timely progression through mitosis. Understanding GO:1902423 is therefore essential for researchers studying cell division, genome stability, and related pathologies.
regulation of attachment of mitotic spindle microtubules to kinetochore At A Glance
| GO ID | GO:1902423 |
|---|---|
| GO term | regulation of attachment of mitotic spindle microtubules to kinetochore |
| Ontology | biological_process |
| Synonym | regulation of attachment of spindle microtubules to kinetochore during mitosis; regulation of attachment of spindle microtubules to kinetochore involved in mitosis; regulation of attachment of spindle microtubules to kinetochore involved in mitotic sister chromatid segregation; regulation of attachment of spindle microtubules to mitotic chromosome; regulation of mitotic attachment of spindle microtubules to kinetochore; regulation of mitotic bipolar attachment |
| Major function | Modulates the attachment of spindle microtubules to kinetochores to ensure accurate chromosome segregation during mitosis. |
| Related processes | Spindle assembly checkpoint, chromosome segregation, mitotic progression. |
| Key regulators | MPS1, Aurora A, Aurora B, PP1, PP6, NDC80 complex, CENP-F, TPX2, EB1. |
| Disease relevance | Chromosomal instability, aneuploidy, cancer, developmental disorders. |
What Is GO:1902423?
GO:1902423 is defined as any process that modulates the frequency, rate or extent of attachment of spindle microtubules to kinetochore involved in mitotic sister chromatid segregation. In simpler terms, it covers all regulatory mechanisms that control how microtubules from the mitotic spindle connect to the kinetochore, a protein structure on chromosomes, to enable their proper segregation during cell division.
Why Is regulation of attachment of mitotic spindle microtubules to kinetochore Important in Cell Biology?
Proper regulation of kinetochore-microtubule attachment is essential for genomic stability. Errors in this process can lead to aneuploidy, a hallmark of cancer and various developmental disorders. The spindle assembly checkpoint monitors attachment status and delays anaphase until all chromosomes are properly attached. Regulatory proteins such as MPS1 and Aurora kinases ensure timely correction of attachment errors, and their dysfunction is linked to tumorigenesis [1,4]. Thus, studying GO:1902423 provides critical insights into basic cell biology and disease mechanisms.
• Ensures accurate chromosome segregation and prevents aneuploidy.
• Spindle assembly checkpoint surveillance relies on proper attachment regulation.
• MPS1 promotes timely spindle bipolarization and prevents attachment errors.
• Aurora A and PP6 regulate NDC80 phosphorylation and spindle size.
• PP1 bound to Spc105 silences the checkpoint and regulates attachment.
• CENP-F influences centromere and kinetochore transcription.
• EB1 decoration of microtubules facilitates lateral attachment.
• Nup107-160 complex controls Aurora B localization and mitotic events.
• Dysregulation leads to chromosomal instability and cancer.
• Targeting these pathways offers potential for anticancer therapies.
What Happens During regulation of attachment of mitotic spindle microtubules to kinetochore?
Initiation of Kinetochore-Microtubule Attachment
In simple terms: This is the first step where microtubules start to connect to the kinetochore.
During early mitosis, the kinetochore assembles on centromeric chromatin and begins to capture spindle microtubules. This process is regulated by kinases such as Aurora B and MPS1, which phosphorylate kinetochore components to prevent premature stable attachments [1,2]. The NDC80 complex forms the core microtubule-binding interface, and its phosphorylation state is controlled by Aurora A and PP6. Proper initiation requires the localization of regulatory proteins like CENP-F and the Nup107-160 complex [3,8].
Error Correction and Bipolar Attachment
In simple terms: The cell fixes incorrect attachments to ensure each chromosome is pulled in the right direction.
Initially, attachments may be lateral or monotelic. Aurora B kinase phosphorylates substrates at the kinetochore to destabilize incorrect attachments, allowing for re-attachment. MPS1 promotes spindle bipolarization, which is crucial for achieving bipolar attachment. PP1, recruited by Spc105/KNL1, counteracts Aurora B to stabilize correct attachments and silence the spindle assembly checkpoint. This dynamic balance ensures that only amphitelic attachments persist.
Spindle Assembly Checkpoint Silencing
In simple terms: The checkpoint is turned off once all chromosomes are properly attached.
The spindle assembly checkpoint (SAC) monitors attachment status and inhibits anaphase until all kinetochores are properly attached. PP1 binding to Spc105 is essential for checkpoint silencing and for regulating kinetochore-microtubule attachment stability. MPS1 activity is also required for SAC function and timely bipolarization. Once attachments are correct, the SAC is silenced, allowing progression to anaphase.
Role of Accessory Factors in Attachment Regulation
In simple terms: Other proteins help fine-tune the attachment process.
The Nup107-160 nucleoporin complex promotes mitotic events by controlling the localization of the chromosome passenger complex, which includes Aurora B. EB1 decorates microtubule lattices to facilitate lateral attachment in certain organisms. CENP-F contributes to FOXM1-mediated transcriptional regulation of centromere and kinetochore genes, indirectly influencing attachment. These accessory factors add layers of regulation to ensure robust attachment.
Key Genes Involved in GO:1902423 regulation of attachment of mitotic spindle microtubules to kinetochore
The following genes and proteins are key regulators of GO:1902423, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| MPS1 | Kinase promoting spindle bipolarization and preventing attachment errors | Studied in oocytes and mitosis; potential target for cancer therapy |
| Aurora A | Regulates NDC80 phosphorylation and spindle size | Implicated in mitotic spindle assembly and cancer |
| Aurora B | Error correction and SAC function | Central to attachment regulation and chromosomal stability |
| PP1 | Phosphatase that silences SAC and stabilizes attachments | Interacts with Spc105/KNL1; key for checkpoint silencing |
| PP6 | Phosphatase regulating Aurora A-TPX2 and NDC80 phosphorylation | Controls mitotic spindle size |
| NDC80 | Core kinetochore component that binds microtubules | Phosphorylation status affects attachment stability |
| CENP-F | Centromere/kinetochore protein involved in transcriptional regulation | Links FOXM1 to centromere/kinetochore gene expression |
| TPX2 | Microtubule-associated protein regulating spindle assembly | Target of PP6 regulation |
| EB1 | Microtubule plus-end tracking protein | Facilitates lateral attachment in Plasmodium |
| Nup107-160 complex | Nucleoporin complex controlling Aurora B localization | Promotes mitotic events |
| Spc105/KNL1 | Kinetochore scaffold that recruits PP1 | Essential for SAC silencing and attachment regulation |
| FOXM1 | Transcription factor regulating mitotic genes | Modulates CENP-F and centromere/kinetochore transcription |
| Bub1 | SAC kinase | Monitors attachment and SAC |
| Mad1/Mad2 | SAC components | Inhibit anaphase until attachment is complete |
| CENP-A | Centromeric histone H3 variant | Specifies kinetochore assembly |
| CENP-B | Centromeric protein | Binds CENP-B box; involved in centromere function |
| CENP-C | Kinetochore protein | Essential for kinetochore assembly |
| CENP-E | Kinesin motor | Facilitates chromosome congression and attachment |
How Is regulation of attachment of mitotic spindle microtubules to kinetochore Regulated?
The process of kinetochore-microtubule attachment is regulated by a complex interplay of kinases and phosphatases. MPS1 kinase activity is required for spindle bipolarization and prevention of attachment errors. Aurora A, in conjunction with TPX2, regulates NDC80 phosphorylation, and PP6 counteracts this to limit spindle size. Aurora B phosphorylates kinetochore substrates to destabilize incorrect attachments, while PP1 recruited by Spc105 dephosphorylates them to stabilize correct attachments and silence the SAC [2,6]. The Nup107-160 complex controls the localization of Aurora B, adding another layer of regulation. Additionally, transcription factors like FOXM1 regulate the expression of centromere and kinetochore components, indirectly influencing attachment.
regulation of attachment of mitotic spindle microtubules to kinetochore and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MPS1 | Cancer, oocyte aneuploidy | Knockout or point mutation in cancer cell lines and oocytes |
| Aurora A | Cancer, mitotic defects | Overexpression and knockout models |
| CENP-F | Cancer, developmental disorders | Knockout and knock-in models |
| Nup107-160 | Nephrotic syndrome, microcephaly | Knockout in cell lines and animal models |
| PP1 | Cancer, checkpoint defects | Point mutation of Spc105 binding site |
Chromosomal Instability and Cancer
Dysregulation of kinetochore-microtubule attachment regulation leads to chromosomal instability (CIN), a hallmark of many cancers. Errors in this process cause aneuploidy, which can promote tumorigenesis. Overexpression of Aurora A and MPS1 is observed in various cancers, and their inhibition is being explored as a therapeutic strategy [1,4]. CENP-F and FOXM1 dysregulation have also been linked to cancer through altered centromere and kinetochore gene expression.
Developmental Disorders
Mutations in genes regulating mitotic attachment can cause developmental disorders characterized by microcephaly and growth retardation. For example, defects in Nup107-160 complex components are associated with nephrotic syndrome and microcephaly. Proper attachment regulation is crucial for neural progenitor proliferation and tissue development.
Infertility and Oocyte Aneuploidy
MPS1 promotes timely spindle bipolarization in oocytes, and its dysfunction leads to attachment errors and aneuploidy, contributing to infertility and miscarriage. Age-related oocyte aneuploidy is often linked to weakened SAC and attachment regulation.
From regulation of attachment of mitotic spindle microtubules to kinetochore-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| What is the role of MPS1 in attachment regulation? | Knockout or kinase-dead point mutation in HeLa cells |
| How does Aurora A phosphorylation of NDC80 affect attachment? | Point mutation of NDC80 phosphorylation sites |
| What is the impact of CENP-F loss on kinetochore gene expression? | Knockout in cancer cell lines |
| How does PP1 binding to Spc105 regulate SAC silencing? | Knock-in of PP1-binding mutant Spc105 |
| Does overexpression of Aurora A cause chromosomal instability? | Overexpression in diploid cell lines |
| What is the role of Nup107-160 in Aurora B localization? | Knockout or knockdown in mitotic cells |
How to Study the regulation of attachment of mitotic spindle microtubules to kinetochore Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Live-cell imaging | Dynamics of kinetochore-microtubule attachment | Assessing real-time attachment errors [1,5] |
| Immunofluorescence | Attachment status and protein localization | Quantifying bipolar attachment [4,6] |
| Co-immunoprecipitation | Protein-protein interactions | Identifying regulatory complexes [4,6] |
| CRISPR screens | Gene function in attachment regulation | Discovery of novel regulators [2,8] |
| Phosphoproteomics | Phosphorylation changes | Mapping kinase substrates |
| RNA-seq | Transcriptional changes | Assessing gene expression after perturbation |
| Proximity ligation assay | In situ protein interactions | Detecting close proximity of regulatory proteins |
| Spindle assembly checkpoint assays | SAC activity | Measuring checkpoint silencing [2,6] |
Live-Cell Imaging
Live-cell imaging using fluorescently tagged kinetochore and microtubule markers allows real-time visualization of attachment dynamics. This method can assess the effects of gene knockouts or mutations on attachment stability and error correction [1,5].
Immunofluorescence and High-Resolution Microscopy
Fixed-cell immunofluorescence with antibodies against kinetochore proteins (e.g., NDC80, CENP-A) and microtubules can quantify attachment states. High-resolution microscopy reveals ultrastructural details of kinetochore-microtubule interfaces [4,6].
Biochemical Assays for Protein Interactions
Co-immunoprecipitation and pull-down assays can identify interactions between regulatory proteins and kinetochore components. Phosphorylation-specific antibodies can assess kinase activity and substrate modification [4,6].
CRISPR-Based Genetic Screens
Genome-wide CRISPR knockout or activation screens can identify novel regulators of kinetochore-microtubule attachment. These screens coupled with phenotypic readouts (e.g., chromosome missegregation) uncover genes involved in GO:1902423 [2,8].
How CRISPR Can Be Used to Study GO:1902423 regulation of attachment of mitotic spindle microtubules to kinetochore
Knockout
CRISPR knockout of genes such as MPS1, Aurora A, or CENP-F can reveal their essential roles in kinetochore-microtubule attachment. Knockout cell lines often exhibit mitotic delays, chromosome misalignment, and aneuploidy, providing direct evidence for gene function in GO:1902423 [1,4,8].
Point Mutation
Introducing point mutations (e.g., kinase-dead MPS1 or phosphorylation-deficient NDC80) allows precise dissection of regulatory phosphorylation events. These models help distinguish between catalytic activity and scaffolding functions [4,6].
Knock-in
Knock-in of tagged or mutant proteins (e.g., GFP-tagged CENP-F or PP1-binding mutant Spc105) enables live-cell imaging and biochemical studies. This approach preserves endogenous regulation and provides insights into dynamic localization and interactions [6,8].
Overexpression
Overexpression of Aurora A or MPS1 can induce chromosomal instability and transform cells, modeling cancer-associated states. Such models are useful for testing targeted inhibitors and understanding dosage effects.
How EDITGENE Supports regulation of attachment of mitotic spindle microtubules to kinetochore Research
Researchers studying regulation of attachment of mitotic spindle microtubules to kinetochore-related genes often need to determine whether a candidate gene is causally involved in attachment regulation or merely correlated with mitotic phenotypes. EDITGENE provides comprehensive CRISPR-based services to enable precise genetic manipulation and functional validation.
Contact EDITGENE today to design your custom CRISPR model for regulation of attachment of mitotic spindle microtubules to kinetochore research.
Frequently Asked Questions About regulation of attachment of mitotic spindle microtubules to kinetochore
What is GO:1902423?
GO:1902423 is a Gene Ontology biological process term defined as any process that modulates the frequency, rate or extent of attachment of spindle microtubules to kinetochore involved in mitotic sister chromatid segregation.
What genes are involved in regulation of attachment of mitotic spindle microtubules to kinetochore?
Key genes include MPS1, Aurora A, Aurora B, PP1, PP6, NDC80, CENP-F, TPX2, EB1, and components of the Nup107-160 complex [1,3,4,6,7,8].
Why is kinetochore-microtubule attachment regulation important?
It ensures accurate chromosome segregation and prevents aneuploidy, which is linked to cancer and developmental disorders.
How does MPS1 regulate attachment?
MPS1 promotes timely spindle bipolarization and prevents kinetochore-microtubule attachment errors, as shown in oocytes.
What role does Aurora A play in this process?
Aurora A, together with TPX2, regulates NDC80 phosphorylation and mitotic spindle size, and is counteracted by PP6.
How is the spindle assembly checkpoint connected to attachment regulation?
The SAC monitors attachment status and delays anaphase until all kinetochores are properly attached; PP1 and MPS1 are key regulators [2,6].
What diseases are associated with defects in this process?
Defects cause chromosomal instability, aneuploidy, cancer, infertility, and developmental disorders such as microcephaly [1,2,3].
What experimental models are used to study GO:1902423?
Common models include CRISPR knockout, point mutation, knock-in, and overexpression cell lines, as well as live-cell imaging and biochemical assays [1,4,6,8].
How can CRISPR help study kinetochore-microtubule attachment?
CRISPR enables precise gene knockout, mutation, or tagging to dissect gene function and regulatory mechanisms in mitosis [1,4,6,8].
What services does EDITGENE offer for this research?
EDITGENE provides knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics services.
Conclusion
GO:1902423 encompasses the critical regulatory processes that ensure proper attachment of spindle microtubules to kinetochores during mitosis. This regulation is orchestrated by a network of kinases, phosphatases, and structural proteins, and its dysfunction leads to chromosomal instability and disease. Advances in CRISPR-based models and imaging technologies continue to unravel the molecular details of this process, offering potential therapeutic targets for cancer and other disorders.
References
- 1. Yoshida S et al.. 2025. MPS1 promotes timely spindle bipolarization to prevent kinetochore-microtubule attachment errors in oocytes.. EMBO J 44(13):3794-3823 PMID: 40467861
- 2. Lischetti T et al.. 2015. Regulation of mitotic progression by the spindle assembly checkpoint.. Mol Cell Oncol 2(1):e970484 PMID: 27308407
- 3. Platani M et al.. 2009. The Nup107-160 nucleoporin complex promotes mitotic events via control of the localization state of the chromosome passenger complex.. Mol Biol Cell 20(24):5260-75 PMID: 19864462
- 4. Sobajima T et al.. 2023. PP6 regulation of Aurora A-TPX2 limits NDC80 phosphorylation and mitotic spindle size.. J Cell Biol 222(5) PMID: 36897279
- 5. Leeds BK et al.. 2023. Mechanical coupling coordinates microtubule growth.. Elife 12 PMID: 38150374
- 6. Roy B et al.. 2019. Delineating the contribution of Spc105-bound PP1 to spindle checkpoint silencing and kinetochore microtubule attachment regulation.. J Cell Biol 218(12):3926-3942 PMID: 31649151
- 7. Yang S et al.. 2023. EB1 decoration of microtubule lattice facilitates spindle-kinetochore lateral attachment in Plasmodium male gametogenesis.. Nat Commun 14(1):2864 PMID: 37208365
- 8. Khurana S et al.. 2024. Contribution of CENP-F to FOXM1-Mediated Discordant Centromere and Kinetochore Transcriptional Regulation.. Mol Cell Biol 44(6):209-225 PMID: 38779933
