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Related Concept Videos

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Condensins

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Condensins are large protein complexes that use ATP to fuel the assembly of chromosomes during mitosis. They transform the tangled, shapeless mass of post-interphase DNA into individualized chromosomes by compacting, organizing, and segregating chromosomal DNA.
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At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
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Cohesins02:20

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Cohesin protein complexes are a molecular glue that holds two sister chromatids together. They play an important role both in mitosis and meiosis. In mitosis, all cohesin complexes present on the chromosomes are removed before the start of the anaphase stage.
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The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
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MCPH1 inhibits Condensin II during interphase by regulating its SMC2-Kleisin interface.

Martin Houlard1, Erin E Cutts2, Muhammad S Shamim3,4,5

  • 1Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

Elife
|December 1, 2021
PubMed
Summary

MCPH1 protein prevents condensin II from compacting DNA during interphase. Deleting MCPH1 in mouse cells causes premature chromosome condensation, revealing condensin II

Keywords:
biochemistrycell biologycell cyclechemical biologychromosomecohesincondensationcondensinhumanmicrocephalinmouse

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Area of Science:

  • Cell Biology
  • Genetics
  • Molecular Biology

Background:

  • Chromosomal DNA morphology dramatically changes between cell cycle interphase and mitosis.
  • Cohesin and condensin are key enzymes regulating DNA topology through loop extrusion.
  • Condensin typically functions during mitosis, while cohesin acts during interphase.

Purpose of the Study:

  • To investigate the mechanism by which MCPH1 (Microcephaly gene) inhibits condensin II activity during interphase.
  • To understand how MCPH1 mutations lead to premature chromosome condensation observed in microcephaly patients.
  • To elucidate the role of MCPH1 in regulating chromosome structure outside of mitosis.

Main Methods:

  • Utilized mouse embryonic stem cells with targeted deletion of the Mcph1 gene.
  • Assessed chromosome condensation, chromatin compartment mixing, and enzyme activity in G1 and G2 phases.
  • Investigated protein-protein interactions between MCPH1 and condensin II subunits (NCAPG2, SMC2, NCAPH2) using biochemical assays.

Main Results:

  • Deletion of Mcph1 in mouse cells resulted in premature formation of compact chromosomes in G1 and G2 phases, even without CDK1 activity.
  • MCPH1 inhibits condensin II by binding to its NCAPG2 subunit via a specific linear motif.
  • MCPH1's inhibitory function is linked to its ability to block condensin II's chromatin association, similar to cohesin regulation.

Conclusions:

  • MCPH1 acts as a crucial interphase inhibitor of condensin II, preventing premature chromosome compaction.
  • The mechanism of MCPH1 inhibition involves direct interaction with condensin II subunits, analogous to WAPL's regulation of cohesin.
  • Dysregulation of this MCPH1-condensin II axis contributes to chromosomal abnormalities seen in microcephaly.