Centrosome age regulates kinetochore microtubule stability and biases chromosome mis-segregation

  1. Ivana Gasic
  2. Purnima Nerurkar
  3. Patrick Meraldi  Is a corresponding author
  1. University of Geneva, Switzerland
  2. Eidgenössische Technische Hochschule Zürich, Switzerland

Abstract

The poles of the mitotic spindle contain one old and one young centrosome. In asymmetric stem cell divisions, the age of centrosomes affects their behaviour and their probability to remain in the stem cell. In contrast, in symmetric divisions old and young centrosomes are thought to behave equally. This hypothesis is, however, untested. Here, we show in symmetrically dividing human cells, that kinetochore-microtubules associated to old centrosomes are more stable than those associated to young centrosomes, and that this difference favors the accumulation of premature end-on attachments that delay the alignment of polar chromosomes at the old centrosome. This differential microtubule stability depends on cenexin, a protein enriched on old centrosomes. It persists throughout mitosis, biasing chromosome segregation in anaphase by causing daughter cells with old centrosomes to retain non-disjoint chromosomes 85% of the time. We conclude that centrosome age imposes via cenexin a functional asymmetry on all mitotic spindles.

Article and author information

Author details

  1. Ivana Gasic

    Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Purnima Nerurkar

    Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Patrick Meraldi

    Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland
    For correspondence
    Patrick.meraldi@unige.ch
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Anna Akhmanova, Utrecht University, Netherlands

Version history

  1. Received: April 2, 2015
  2. Accepted: August 18, 2015
  3. Accepted Manuscript published: August 19, 2015 (version 1)
  4. Version of Record published: September 23, 2015 (version 2)

Copyright

© 2015, Gasic et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,696
    Page views
  • 672
    Downloads
  • 27
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ivana Gasic
  2. Purnima Nerurkar
  3. Patrick Meraldi
(2015)
Centrosome age regulates kinetochore microtubule stability and biases chromosome mis-segregation
eLife 4:e07909.
https://doi.org/10.7554/eLife.07909

Share this article

https://doi.org/10.7554/eLife.07909

Further reading

    1. Cell Biology
    2. Neuroscience
    Haibin Yu, Dandan Liu ... Kai Yuan
    Research Article

    O-GlcNAcylation is a dynamic post-translational modification that diversifies the proteome. Its dysregulation is associated with neurological disorders that impair cognitive function, and yet identification of phenotype-relevant candidate substrates in a brain-region specific manner remains unfeasible. By combining an O-GlcNAc binding activity derived from Clostridium perfringens OGA (CpOGA) with TurboID proximity labeling in Drosophila, we developed an O-GlcNAcylation profiling tool that translates O-GlcNAc modification into biotin conjugation for tissue-specific candidate substrates enrichment. We mapped the O-GlcNAc interactome in major brain regions of Drosophila and found that components of the translational machinery, particularly ribosomal subunits, were abundantly O-GlcNAcylated in the mushroom body of Drosophila brain. Hypo-O-GlcNAcylation induced by ectopic expression of active CpOGA in the mushroom body decreased local translational activity, leading to olfactory learning deficits that could be rescued by dMyc overexpression-induced increase of protein synthesis. Our study provides a useful tool for future dissection of tissue-specific functions of O-GlcNAcylation in Drosophila, and suggests a possibility that O-GlcNAcylation impacts cognitive function via regulating regional translational activity in the brain.

    1. Cancer Biology
    2. Cell Biology
    Ibtisam Ibtisam, Alexei F Kisselev
    Short Report

    Rapid recovery of proteasome activity may contribute to intrinsic and acquired resistance to FDA-approved proteasome inhibitors. Previous studies have demonstrated that the expression of proteasome genes in cells treated with sub-lethal concentrations of proteasome inhibitors is upregulated by the transcription factor Nrf1 (NFE2L1), which is activated by a DDI2 protease. Here, we demonstrate that the recovery of proteasome activity is DDI2-independent and occurs before transcription of proteasomal genes is upregulated but requires protein translation. Thus, mammalian cells possess an additional DDI2 and transcription-independent pathway for the rapid recovery of proteasome activity after proteasome inhibition.