PT  - JOURNAL ARTICLE
AU  - Juanita C. Limas
AU  - Amiee N. Littlejohn
AU  - Amy M. House
AU  - Katarzyna M. Kedziora
AU  - Dalia Fleifel
AU  - Brandon L. Mouery
AU  - Andrea Walens
AU  - Maria M. Aleman
AU  - Daniel Dominguez
AU  - Jeanette Gowen Cook
TI  - Quantitative Profiling of Adaptation to Cyclin E Overproduction
AID  - 10.1101/2021.07.26.453751
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.07.26.453751
4099  - http://biorxiv.org/content/early/2021/07/27/2021.07.26.453751.short
4100  - http://biorxiv.org/content/early/2021/07/27/2021.07.26.453751.full
AB  - Cyclin E/CDK2 drives cell cycle progression from G1 to S phase. Cyclin E overproduction is toxic to mammalian cells, although the gene encoding cyclin E (CCNE1) is overexpressed in some cancers. It is not yet understood how cancer cells tolerate high levels of cyclin E. To address this question, we extensively characterized non-transformed epithelial cells subjected to chronic cyclin E overproduction. Cells overproducing human cyclin E briefly experienced truncated G1 phases, then consistently endured a transient period of DNA replication origin underlicensing, replication stress, and severely impaired proliferation. Individual cells displayed substantial intercellular heterogeneity in both cell cycle dynamics and CDK activity. Each of these phenotypes improved rapidly despite maintaining high cyclin E-associated activity. Transcriptome analysis revealed that adapted cells downregulated a cohort of G1-regulated genes. These cells also shared at least one unique change also found in breast tumors that overproduce cyclin E, expression of the cancer/testis antigen HORMAD1. Withdrawing cyclin E induction partially reversed the intermediate licensing phenotype of adapted cells indicating that adaptation is at least partly independent of genetic alterations. This study provides evidence that mammalian cyclin E/CDK inhibits origin licensing by an indirect mechanism through premature S phase onset. It serves as an example of specific oncogene adaptation that can identify key molecular changes during tumorigenesis.Competing Interest StatementThe authors have declared no competing interest.