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.
Highlights
Metazoan DNA replication requires initiation at thousands of DNA replication origins during S phase of every cell cycle
These findings demonstrate that the rate of minichromosome maintenance (MCM) loading is subject to developmental regulation, and we suggest that rapid origin licensing is a new hallmark of pluripotency
One possibility is that cells with short G1 phases load MCM at the same rate as cells with long G1 phases resulting in less total loaded MCM
Summary
Metazoan DNA replication requires initiation at thousands of DNA replication origins during S phase of every cell cycle. Stem cells divide faster than their specialized descendants, and have a much shorter G1 phase too These cells still manage to load enough helicases to copy their DNA. Altering the levels of the proteins changed how quickly the enzymes were loaded and how the cells behaved – for example, slowing down the loading of helicases made the stem cells specialize quicker. These findings show that the processes of cell differentiation and DNA replication are closely linked. These findings demonstrate that the rate of MCM loading is subject to developmental regulation, and we suggest that rapid origin licensing is a new hallmark of pluripotency
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