Abstract
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.
Highlights
From an evolutionary perspective, individuals that give rise to the highest number of progeny are considered to be the fittest
We further show that the ability to enter this slow-cycling state protects cells from further stress, consistent with its association with drug resistance
In multiple primary, immortalized but non-transformed, and cancerous human cells, we previously reported that a majority of cells commits to another cell cycle soon after mitosis, marked by increasing CDK2 activity and hyperphosphorylated Rb (CDK2inc cells), while a separate subpopulation enters a transient G0/quiescence marked by low CDK2 activity, hypophosphorylated Rb, and declining Ki67 levels (CDK2low cells) [10,11,12]
Summary
Individuals that give rise to the highest number of progeny are considered to be the fittest. Proliferation rate is often highly variable, even in a genetically identical population in optimal growth conditions This heterogeneity is marked by the presence of a small population of slow-cycling cells observed in bacteria [1], yeast [2], and human cells [3,4,5]. In multiple primary, immortalized but non-transformed, and cancerous human cells, we previously reported that a majority of cells commits to another cell cycle soon after mitosis, marked by increasing CDK2 activity and hyperphosphorylated Rb (CDK2inc cells), while a separate subpopulation enters a transient G0/quiescence marked by low CDK2 activity, hypophosphorylated Rb, and declining Ki67 levels (CDK2low cells) [10,11,12] These cells can later re-enter the cell cycle by increasing CDK2 activity, indicating the reversibility of this state [10,13]. We refer to this unprompted entry into the CDK2low state as “spontaneous G0” or “spontaneous quiescence,” to contrast with canonical quiescent states, in which cells are forced into quiescence by serum starvation or contact inhibition [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
