Title: Stochastic Endogenous Replication Stress Causes ATR-Triggered Fluctuations in CDK2 Activity that Dynamically Adjust Global DNA Synthesis Rates.

Authors: Daigh, Leighton H; Liu, Chad; Chung, Mingyu; Cimprich, Karlene A; Meyer, Tobias

Published In Cell Syst, (2018 07 25)

Abstract: Faithful DNA replication is challenged by stalling of replication forks during S phase. Replication stress is further increased in cancer cells or in response to genotoxic insults. Using live single-cell image analysis, we found that CDK2 activity fluctuates throughout an unperturbed S phase. We show that CDK2 fluctuations result from transient ATR signals triggered by stochastic replication stress events. In turn, fluctuating endogenous CDK2 activity causes corresponding decreases and increases in DNA synthesis rates, linking changes in stochastic replication stress to fluctuating global DNA replication rates throughout S phase. Moreover, cells that re-enter the cell cycle after mitogen stimulation have increased CDK2 fluctuations and prolonged S phase resulting from increased replication stress-induced CDK2 suppression. Thus, our study reveals a dynamic control principle for DNA replication whereby CDK2 activity is suppressed and fluctuates throughout S phase to continually adjust global DNA synthesis rates in response to recurring stochastic replication stress events.

PubMed ID: 29909278

MeSH Terms: Ataxia Telangiectasia Mutated Proteins/genetics; Ataxia Telangiectasia Mutated Proteins/metabolism*; Cell Cycle Proteins/genetics; Cell Cycle/physiology; Cell Division; Cell Line; Cyclin-Dependent Kinase 2/metabolism*; Cyclin-Dependent Kinase 2/physiology; Cyclin-Dependent Kinases/genetics; DNA Damage; DNA Replication; DNA-Binding Proteins/genetics; DNA/biosynthesis*; Humans; MCF-7 Cells; S Phase/physiology; Single-Cell Analysis/methods