Temporal myc dynamics permit mitotic bypass, promoting polyploid phenotypes

High Myc phenotypes are extensively documented in the hyperproliferative cell cycle of cancer cells, as well as non-proliferative endoreplication cycles engaged during normal development and stress response. Notably, endoreplication in cancer produces chemotherapy resistant polyploid cells, necessitating a clearer understanding of altered cell cycle regulation that uncouples DNA replication and mitotic cell division. The c-Myc oncogene is a well-established transcriptional regulator of cell cycle progression and has been extensively published as an essential driver of the G1/S transition. Beyond S phase, Myc transcriptionally activates the proteins that drive mitotic entry. Sustained activation of Myc through the cell cycle transcriptionally couples DNA replication and mitotic cell division. Based on the literature in this field, we propose a new model of temporal regulation of Myc activity that serves to either couple or uncouple these two processes, determining cell cycle fate – proliferation or polyploidy. The mitotic cell cycle requires two pulses of Myc activity – the first driving the G1/S transition and the second driving the G2/M transition. During mitosis, Myc activity must be silenced to achieve high-fidelity division. Absence of the second activity pulse during G2 results in the downregulation of the proteins essential for mitotic entry and permits premature activation of APC/C, inducing mitotic bypass. A subsequent rise of Myc activity following mitotic bypass permits genome re-replication, driving polyploid phenotypes. This model serves to provide a new level of understanding to the global regulation of S phase-mitosis coupling, as well as a new lens to view low Myc phenotypes. • Myc activity promotes both hyperproliferative and non-proliferative polyploid phenotypes. • Proposed model of temporal Myc regulation reconciles Myc-driven mitotic and endoreplication cell cycle mechanisms. • The mitotic cell cycle is regulated by two Myc pulses: the first drives G1/S, and the second drives G2/M. • Absence of the G2 Myc pulse causes mitotic bypass; a subsequent pulse permits genome re-replication and polyploidy.