PT  - JOURNAL ARTICLE
AU  - Jacob Peter Matson
AU  - Raluca Dumitru
AU  - Phillip Coryell
AU  - Ryan M Baxley
AU  - Weili Chen
AU  - Kirk Twaroski
AU  - Beau R. Webber
AU  - Jakub Tolar
AU  - Anja-Katrin Bielinsky
AU  - Jeremy Purvis
AU  - Jeanette Gowen Cook
TI  - Rapid DNA Replication Origin Licensing Protects Stem Cell Pluripotency
AID  - 10.1101/164368
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 164368
4099  - http://biorxiv.org/content/early/2017/07/17/164368.short
4100  - http://biorxiv.org/content/early/2017/07/17/164368.full
AB  - 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.