1. Cell Biology
  2. Chromosomes and Gene Expression
Download icon

Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age effect

  1. Agata P Zielinska
  2. Zuzana Holubcova
  3. Martyn Blayney
  4. Kay Elder
  5. Melina Schuh  Is a corresponding author
  1. Medical Research Council, United Kingdom
  2. Bourn Hall Clinic, United Kingdom
Research Article
  • Cited 62
  • Views 3,316
  • Annotations
Cite this article as: eLife 2015;4:e11389 doi: 10.7554/eLife.11389
Voice your concerns about research culture and research communication: Have your say in our 7th annual survey.

Abstract

Aneuploidy in human eggs is the leading cause of pregnancy loss and Down's syndrome. Aneuploid eggs result from chromosome segregation errors when an egg develops from a progenitor cell, called an oocyte. The mechanisms that lead to an increase in aneuploidy with advanced maternal age are largely unclear. Here, we show that many sister kinetochores in human oocytes are separated and do not behave as a single functional unit during the first meiotic division. Having separated sister kinetochores allowed bivalents to rotate by 90 degrees on the spindle and increased the risk of merotelic kinetochore-microtubule attachments. Advanced maternal age led to an increase in sister kinetochore separation, rotated bivalents and merotelic attachments. Chromosome arm cohesion was weakened, and the fraction of bivalents that precociously dissociated into univalents was increased. Together, our data reveal multiple age-related changes in chromosome architecture that could explain why oocyte aneuploidy increases with advanced maternal age.

Article and author information

Author details

  1. Agata P Zielinska

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Zuzana Holubcova

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Martyn Blayney

    Bourn Hall Clinic, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Kay Elder

    Bourn Hall Clinic, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Melina Schuh

    Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    For correspondence
    mschuh@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: The use of immature unfertilized human oocytes in this study has been approved by the UK's National Research Ethics Service under the REC reference 11/EE/0346; IRAS Project ID 84952. Immature unfertilized oocytes were donated by women receiving assisted reproduction treatment at Bourn Hall Clinic (Cambridge, UK).

Reviewing Editor

  1. Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany

Publication history

  1. Received: September 4, 2015
  2. Accepted: December 9, 2015
  3. Accepted Manuscript published: December 15, 2015 (version 1)
  4. Accepted Manuscript updated: December 16, 2015 (version 2)
  5. Version of Record published: February 2, 2016 (version 3)

Copyright

© 2015, Zielinska 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

  • 3,316
    Page views
  • 880
    Downloads
  • 62
    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)

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

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

  1. Further reading

Further reading

    1. Cell Biology
    David W Sanders et al.
    Research Article Updated

    Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Asha Mary Joseph et al.
    Research Article Updated

    Translesion synthesis (TLS) is a highly conserved mutagenic DNA lesion tolerance pathway, which employs specialized, low-fidelity DNA polymerases to synthesize across lesions. Current models suggest that activity of these polymerases is predominantly associated with ongoing replication, functioning either at or behind the replication fork. Here we provide evidence for DNA damage-dependent function of a specialized polymerase, DnaE2, in replication-independent conditions. We develop an assay to follow lesion repair in non-replicating Caulobacter and observe that components of the replication machinery localize on DNA in response to damage. These localizations persist in the absence of DnaE2 or if catalytic activity of this polymerase is mutated. Single-stranded DNA gaps for SSB binding and low-fidelity polymerase-mediated synthesis are generated by nucleotide excision repair (NER), as replisome components fail to localize in the absence of NER. This mechanism of gap-filling facilitates cell cycle restoration when cells are released into replication-permissive conditions. Thus, such cross-talk (between activity of NER and specialized polymerases in subsequent gap-filling) helps preserve genome integrity and enhances survival in a replication-independent manner.