SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis
- 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
Nathaniel P Rogers
Marina V Pryzhkova
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.
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).
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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SMC5/6 is required for replication fork stability and faithful chromosome segregation during neurogenesis
eLife 9:e61171.
https://doi.org/10.7554/eLife.61171
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