Spontaneously slow-cycling subpopulations of human cells originate from activation of stress-response pathways

PLoS Biol. 2019 Mar 13;17(3):e3000178. doi: 10.1371/journal.pbio.3000178. eCollection 2019 Mar.


Slow-cycling subpopulations exist in bacteria, yeast, and mammalian systems. In the case of cancer, slow-cycling subpopulations have been proposed to give rise to drug resistance. However, the origin of slow-cycling human cells is poorly studied, in large part due to lack of markers to identify these rare cells. Slow-cycling cells pass through a noncycling period marked by low CDK2 activity and high p21 levels. Here, we use this knowledge to isolate these naturally slow-cycling cells from a heterogeneous population and perform RNA sequencing to delineate the transcriptome underlying the slow-cycling state. We show that cellular stress responses-the p53 transcriptional response and the integrated stress response (ISR)-are the most salient causes of spontaneous entry into the slow-cycling state. Finally, we show that cells' ability to enter the slow-cycling state enhances their survival in stressful conditions. Thus, the slow-cycling state is hardwired to stress responses to promote cellular survival in unpredictable environments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Survival / genetics
  • Cell Survival / physiology*
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism
  • Humans
  • Neoplasms / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*


  • Cyclin-Dependent Kinase 2