E2F-dependent genetic oscillators control endoreplication

Abstract

Polyploidy is an integral part of development and is associated with cellular stress, aging and pathological conditions. The endoreplication cycle, comprised of successive alternations of G and S phases without cell division, is widely employed to produce polyploid cells. The endocycle is driven by continuous oscillations of Cyclin E/Cdk2 activity, which is governed by E2F transcription factors. In this study, we provide mechanistic insight on how E2F-dependent Cdk oscillations during endocycles are maintained in Drosophila salivary glands. Genetic experiments revealed that an alternative splicing isoform of E2F1, E2F1b, regulates the circuitry of timely S phase entry and exit by activating a subset of E2F target genes. E2F1b regulates the Drosophila ortholog of p27 CIP/KIP -like Cdk inhibitor Dacapo to precisely time S phase entry by controlling the CycE/Cdk2 activity threshold. Upon entry to S phase, E2F1bdependent PCNA expression establishes a negative feedback loop through the PIP box-mediated degradation of E2F1. Overall, our study uncovers a network of E2Fdependent genetic oscillators that are critical for the periodic transition between G and S phases during endoreplication.