Control of cell cycle commitment by APC-C-Cdh1

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Cells were long thought to irreversibly commit to a round of cell division at a specific point in G1 phase, thus ensuring that cells maintain genome integrity. However, our work over the past several years has demonstrated a number of different conditions that cause cells to de-commit from the cell cycle in later phases, including S and G2 phase. This phenomenon leads to genome instability and aneuploidy, which can be hallmarks of aggressive cancers. This project leverages our platform of live-cell imaging and single-cell tracking to watch as cells progress through the cell cycle. By exposing cells to various types of stresses and drugs used in the treatment of cancer, we can determine how and why cells exit the cell cycle prematurely. We recently demonstrated how clinically relevant CDK4/6 inhibitors can cause a fraction of cells to enter into a G0-like state, but with 4N DNA content. We are currently investigating the long-term consequences of this drug-induced state. Furthermore, DNA damage is known to cause cells in S and G2 phase to prematurely exit the cell cycle in a similar manner to CDK4/6 inhibitors. This project aims to investigate the molecular mechanism underlying DNA damage-mediated cell cycle exit with the aim to develop treatments that prevent these cells from re-entering the cell cycle and becoming aneuploid.