Research ArticleCELL CYCLE

Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch

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Science Advances  26 May 2017:
Vol. 3, no. 5, e1700298
DOI: 10.1126/sciadv.1700298

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Abstract

Cell cycle regulators are increasingly implicated in cell fate decisions, such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. We studied an S phase–dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. The switch to differentiation entails rapid down-regulation of p57KIP2 with a consequent global increase in replication fork speed and an abruptly shorter S phase. Our work suggests that cell cycles with specialized global DNA replication dynamics are integral to the maintenance of specific cell states and to cell fate decisions.

Keywords
  • cell cycle
  • CDK inhibitors
  • replication
  • differentiation
  • cell fate decision
  • self renewal
  • erythropoiesis
  • hematopoiesis

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