Projects per year
Abstract
During late mitosis and the early G1 phase, the origins of replication are licensed by binding to double hexamers of MCM2-7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. 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 the 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 G 1 length, characterized 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 phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.
Original language | English |
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Pages (from-to) | 1667-1685 |
Number of pages | 19 |
Journal | Journal of Cell Biology |
Volume | 217 |
Issue number | 5 |
DOIs | |
Publication status | Published - 7 May 2018 |
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Projects
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Understanding the Cellular Response to Replication Inhibition (Senior Investigator Award)
1/09/12 → 28/02/21
Project: Research
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Development of Live Tissue Imaging Capabilities Using Multiphoton Confocal Microscopy
Muller, A., Nathke, I., Storey, K. & Weijer, K.
30/06/14 → 29/06/19
Project: Research
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Strategic Award: Wellcome Trust Technology Platform
Blow, J., Lamond, A. & Owen-Hughes, T.
1/01/13 → 30/09/18
Project: Research