SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis

  1. Alisa Atkins
  2. Michelle J Xu
  3. Maggie Li
  4. Nathaniel P Rogers
  5. Marina V Pryzhkova  Is a corresponding author
  6. Philip W Jordan  Is a corresponding author
  1. Johns Hopkins Bloomberg School of Public Health, United States

Abstract

Mutations of SMC5/6 components cause developmental defects, including primary microcephaly. To model neurodevelopmental defects, we engineered a mouse wherein Smc5 is conditionally knocked out (cKO) in the developing neocortex. Smc5 cKO mice exhibited neurodevelopmental defects due to neural progenitor cell (NPC) apoptosis, which led to reduction in cortical layer neurons. Smc5 cKO NPCs formed DNA bridges during mitosis and underwent chromosome missegregation. SMC5/6 depletion triggers a CHEK2-p53 DNA damage response, as concomitant deletion of the Trp53 tumor suppressor or Chek2 DNA damage checkpoint kinase rescued Smc5 cKO neurodevelopmental defects. Further assessment using Smc5 cKO and auxin-inducible degron systems demonstrated that absence of SMC5/6 leads to DNA replication stress at late-replicating regions such as pericentromeric heterochromatin regions. In summary, SMC5/6 is important for completion of DNA replication prior to entering mitosis, which ensures accurate chromosome segregation. Thus, SMC5/6 functions are critical in highly proliferative stem cells during organism development.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Alisa Atkins

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Michelle J Xu

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maggie Li

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1047-1554
  4. Nathaniel P Rogers

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, New Orleans, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0411-5249
  5. Marina V Pryzhkova

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    For correspondence
    mpryzhk1@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3462-5768
  6. Philip W Jordan

    Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    For correspondence
    pjordan8@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4890-2647

Funding

National Institute of General Medical Sciences (R01GM11755)

  • Philip W Jordan

National Institutes of Health (R21OD023720)

  • Philip W Jordan

National Institute of Neurological Disorders and Stroke (R03NS106486)

  • Philip W Jordan

Johns Hopkins University (Catalyst Award)

  • Philip W Jordan

National Cancer Institute (T32CA009110)

  • Michelle J Xu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Kevin Struhl, Harvard Medical School, United States

Ethics

Animal experimentation: All mice were bred at Johns Hopkins University (JHU, Baltimore, MD) in accordance with the National Institutes of Health and U.S. Department of Agriculture criteria and protocols for their care and use were approved by the Institutional Animal Care and Use Committees (IACUC) of JHU (Protocol number = MO19H08).

Version history

  1. Received: July 16, 2020
  2. Accepted: November 16, 2020
  3. Accepted Manuscript published: November 17, 2020 (version 1)
  4. Version of Record published: December 8, 2020 (version 2)

Copyright

© 2020, Atkins 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.

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  1. Alisa Atkins
  2. Michelle J Xu
  3. Maggie Li
  4. Nathaniel P Rogers
  5. Marina V Pryzhkova
  6. Philip W Jordan
(2020)
SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis
eLife 9:e61171.
https://doi.org/10.7554/eLife.61171

Share this article

https://doi.org/10.7554/eLife.61171

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