Journal
JOURNAL OF CELL BIOLOGY
Volume 217, Issue 5, Pages 1667-1685Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201708023
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Funding
- Wellcome Trust [097945/B/11/Z, 101468/Z/13/Z, WT096598MA]
- Cancer Research UK [C430/A11243, C303/A14301]
- Medical Research Council
- Wellcome Trust [101468/Z/13/Z] Funding Source: Wellcome Trust
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During late mitosis and the early G(1) 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 G(1) entry. We propose that the unlicensed G(1) phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.
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