Study cell cycle regulation in dormant tumor cells

Division Of Basic Sciences - Nci

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Abstract

The overall goal of this project is to investigate mechanisms underlying irreversible cell cycle exit. We recently uncovered the molecular mechanism underlying APC/C inactivation at the G1/S transition and showed how this molecular switch controls irreversible cell cycle entry. However, several studies have recently shown that APC/C re-activation in G2 phase after DNA damage also plays a critical role in the decision to undergo senescence, which is defined as an irreversible cell cycle exit. The molecular mechanism underlying this APC/C re-activation is not currently known. Using our APC/C and CDK2 biosensors, our data shows that APC/C only re-activates in response to DNA damage when CDK2 activity is suppressed to lower levels than is needed in G1 phase to inactivate APC/C. This critical observation indicates APC/C re-activation demonstrates hysteresis, a key feature in irreversible fate transitions, and could therefore be the critical event underlying senescence entry. We are currently investigating the mechanism underlying Emi1 suppression in response to DNA damage. In addition, we are investigating additional mechanisms that may maintain senescence. Using our time-lapse imaging capabilities, we can induce senescence with a combination of MEK and CDK4/6 inhibitors and follow cells as they undergo senescence. By removing the initiating stimulus at various points, we will identify the point of irreversibility in senescence. We also identify additional genes necessary to mediate this irreversibility in an unbiased manner using our suite of live-cell reporters and a genome-wide CRISPR screen.