1. Chromosomes and Gene Expression
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Rapid DNA replication origin licensing protects stem cell pluripotency

  1. Jacob Peter Matson
  2. Raluca Dumitru
  3. Philip Coryell
  4. Ryan M Baxley
  5. Weili Chen
  6. Kirk Twaroski
  7. Beau R Webber
  8. Jakub Tolar
  9. Anja-Katrin Bielinsky
  10. Jeremy E Purvis
  11. Jeanette Gowen Cook  Is a corresponding author
  1. University of North Carolina at Chapel Hill, United States
  2. University of North Carolina at Chapel Hill, United States
  3. University of Minnesota, United States
  4. University of Minnesota, United States
Research Article
  • Cited 34
  • Views 4,488
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Cite this article as: eLife 2017;6:e30473 doi: 10.7554/eLife.30473

Abstract

Complete and robust human genome duplication requires loading MCM helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single cell analyses we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation towards all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.

Article and author information

Author details

  1. Jacob Peter Matson

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Raluca Dumitru

    Human Pluripotent Stem Cell Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Philip Coryell

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Ryan M Baxley

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Weili Chen

    Stem Cell Institute, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Kirk Twaroski

    Stem Cell Institute, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Beau R Webber

    Stem Cell Institute, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Jakub Tolar

    Stem Cell Institute, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0957-4380

  9. Anja-Katrin Bielinsky

    Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Jeremy E Purvis

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6963-0524

  11. Jeanette Gowen Cook

    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    For correspondence
    jean_cook@med.unc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0849-7405

Funding

National Institutes of Health (Research Grant GM074917)

  • Anja-Katrin Bielinsky

National Science Foundation (Graduate Student Research Fellowship DGE1144081)

  • Jacob Peter Matson

W. M. Keck Foundation (Research Grant)

  • Jeremy E Purvis
  • Jeanette Gowen Cook

National Institutes of Health (Training Grant T32CA009138)

  • Ryan M Baxley

National Institutes of Health (Research Grant GM083024)

  • Jeanette Gowen Cook

National Institutes of Health (Research Grant DP2HD091800)

  • Jeremy E Purvis

National Institutes of Health (Research Grant GM102413)

  • Jeanette Gowen Cook

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

Reviewing Editor

  1. Bruce Stillman, Cold Spring Harbor Laboratory, United States

Publication history

  1. Received: July 17, 2017
  2. Accepted: November 16, 2017
  3. Accepted Manuscript published: November 17, 2017 (version 1)
  4. Version of Record published: December 7, 2017 (version 2)
  5. Version of Record updated: June 5, 2019 (version 3)

Copyright

© 2017, Matson 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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