Speedy Cell Cycle Slows Stem Cell Differentiation

A team of cell biologists has found that the ability of pluripotent stem cells to remain in an undifferentiated state is linked to the length of time the cell spends in the G1 phase of cell division.

All dividing cells must first unwind their DNA so that it can be copied. To achieve this, cells load DNA-unwinding enzymes called helicases onto their DNA during the part of the cell cycle known as G1 phase. Cells must load enough helicase enzymes to ensure that their DNA is copied completely and in time. Stem cells divide faster than their specialized descendants, and have a much shorter G1 phase, as well. Yet these cells still manage to load enough helicases to copy their DNA. Little is known about how the amount, rate, and timing of helicase loading vary between cells that divide at different speeds.

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. Investigators at the University of North Carolina (Chapel Hill, USA) utilized single-cell flow cytometry to measure MCM loading rates in asynchronous populations of pluripotent and differentiated cells.

Results published in the November 17, 2017, online edition of the journal eLife revealed that pluripotent stem cells with naturally short G1 phases loaded MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation toward all lineages, MCM loading slowed concurrently with G1 lengthening, revealing developmental control of MCM loading. Rapid licensing in stem cells was caused by accumulation of the MCM loading protein, Cdt1 (DNA replication factor Cdt1). Prematurely slowing MCM loading in pluripotent cells not only lengthened G1 but also accelerated differentiation. Thus, rapid origin licensing was an intrinsic characteristic of stem cells that contributed to pluripotency maintenance.

"Studies like this help explain the underlying biology of rapidly dividing cells and may inform the development of future therapies, for example stem cell therapies or cancer treatments," said study senior author Dr. Jean Cook, professor of biochemistry and biophysics at the University of North Carolina. "We suspect that rapid MCM loading is an important aspect of how cancer cells manage to grow fast without excessively damaging their DNA. It is a target worth pursuing."

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