Rapid DNA replication origin licensing protects stem cell pluripotency
- University of North Carolina at Chapel Hill, United States
- University of North Carolina at Chapel Hill, United States
- University of Minnesota, United States
- University of Minnesota, United States
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
Jeanette Gowen Cook
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.
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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Rapid DNA replication origin licensing protects stem cell
pluripotency
eLife 6:e30473.
https://doi.org/10.7554/eLife.30473
