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Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells

T.D. Carroll, I.P. Newton, Y. Chen, J.J. Blow, View ORCID ProfileI. Näthke
doi: https://doi.org/10.1101/177477
T.D. Carroll
1Cell & Developmental Biology, University of Dundee, Dundee, Scotland, UK, DD15EH
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I.P. Newton
1Cell & Developmental Biology, University of Dundee, Dundee, Scotland, UK, DD15EH
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Y. Chen
1Cell & Developmental Biology, University of Dundee, Dundee, Scotland, UK, DD15EH
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J.J. Blow
2Centre for Gene Regulation and Expression, University of Dundee, Dundee, Scotland, UK, DD15EH
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  • For correspondence: j.j.blow@dundee.ac.uk i.s.nathke@dundee.ac.uk
I. Näthke
1Cell & Developmental Biology, University of Dundee, Dundee, Scotland, UK, DD15EH
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  • ORCID record for I. Näthke
  • For correspondence: j.j.blow@dundee.ac.uk i.s.nathke@dundee.ac.uk
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ABSTRACT

During late mitosis and early G1, replication origins are licensed for replication by binding to double hexamers of MCM2-7. Here, we investigate how licensing and proliferative commitment are coupled in the small-intestinal epithelium. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5(+) stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem-cells is caused by an increased G1 length, characterised by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost In Apc mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 14, 2018.
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Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells
T.D. Carroll, I.P. Newton, Y. Chen, J.J. Blow, I. Näthke
bioRxiv 177477; doi: https://doi.org/10.1101/177477
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Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells
T.D. Carroll, I.P. Newton, Y. Chen, J.J. Blow, I. Näthke
bioRxiv 177477; doi: https://doi.org/10.1101/177477

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