RT Journal Article SR Electronic T1 Quantitative profiling of adaptation to cyclin E overproduction JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201378 DO 10.26508/lsa.202201378 VO 5 IS 5 A1 Juanita C Limas A1 Amiee N Littlejohn A1 Amy M House A1 Katarzyna M Kedziora A1 Brandon L Mouery A1 Boyang Ma A1 Dalia Fleifel A1 Andrea Walens A1 Maria M Aleman A1 Daniel Dominguez A1 Jeanette Gowen Cook YR 2022 UL https://www.life-science-alliance.org/content/5/5/e202201378.abstract AB Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Despite the toxicity of cyclin E overproduction in mammalian cells, the cyclin E gene is overexpressed in some cancers. To further understand how cells can tolerate high cyclin E, we characterized non-transformed epithelial cells subjected to chronic cyclin E overproduction. Cells overproducing cyclin E, but not cyclins D or A, briefly experienced truncated G1 phases followed by a transient period of DNA replication origin underlicensing, replication stress, and impaired proliferation. Individual cells displayed substantial intercellular heterogeneity in cell cycle dynamics and CDK activity. Each phenotype improved rapidly despite high cyclin E–associated activity. Transcriptome analysis revealed adapted cells down-regulated a cohort of G1-regulated genes. Withdrawing cyclin E from adapted cells only partially reversed underlicensing indicating that adaptation is at least partly non-genetic. This study provides evidence that mammalian cyclin E/CDK inhibits origin licensing indirectly through premature S phase onset and provides mechanistic insight into the relationship between CDKs and licensing. It serves as an example of oncogene adaptation that may recapitulate molecular changes during tumorigenesis.