Sustained ERK Signaling Promotes G2 Cell Cycle Exit and primes cells for Whole Genome Duplication

Whole genome duplication (WGD) is a frequent event in cancer evolution that fuels chromosomal instability. WGD can result from mitotic errors or endoreduplication (two consecutive S-phase rounds without an intervening mitosis). However, the molecular mechanisms that drive WGD remain unclear. Here we use controllable oncogene expression and live single cell analysis to characterize cell cycle dynamics upon aberrant Ras-ERK signaling. We find that sustained ERK signaling leads to reactivation of the APC/C in G2 resulting in tetraploid G0-like cells that are primed for WGD. This process is independent of DNA damage or p53 but dependent on p21. Transcriptomics analysis and live cell imaging showed that constitutive ERK activity promotes p21 expression, which is necessary and sufficient to inhibit CDK activity and prematurely activate the Anaphase Promoting Complex (APC/C). Finally, either loss of p53 or reduced ERK signaling allowed endoreduplication reaching 8C DNA content. Thus, sustained ERK signaling-induced G2 cell cycle exit represents an alternative cell cycle path leading to whole genome duplication.