Rapid DNA Replication Origin Licensing Protects Stem Cell Pluripotency

Overview

Journal Elife

Specialty Biology

Date 2017 Nov 18

PMID 29148972

Citations 54

Authors

Jacob Peter Matson

Raluca Dumitru

Philip Coryell

Ryan M Baxley

Weili Chen

Kirk Twaroski

Beau R Webber

Jakub Tolar

Anja-Katrin Bielinsky

Jeremy E Purvis

Jeanette Gowen Cook

Affiliations

Soon will be listed here.

Abstract

Complete and robust human genome duplication requires loading minichromosome maintenance (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 toward 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.

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