Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing

Hongqing Liang, Alessandro Esposito, Siddharth De, Suzan Ber, Philippe Collin, Uttam Surana and Ashok R. Venkitaraman ()
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Hongqing Liang: Medical Research Council Cancer Unit, University of Cambridge, Hills Road
Alessandro Esposito: Medical Research Council Cancer Unit, University of Cambridge, Hills Road
Siddharth De: Medical Research Council Cancer Unit, University of Cambridge, Hills Road
Suzan Ber: Medical Research Council Cancer Unit, University of Cambridge, Hills Road
Philippe Collin: Gurdon Institute, University of Cambridge
Uttam Surana: Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Biopolis Drive
Ashok R. Venkitaraman: Medical Research Council Cancer Unit, University of Cambridge, Hills Road

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract The G2 checkpoint monitors DNA damage, preventing mitotic entry until the damage can be resolved. The mechanisms controlling checkpoint recovery are unclear. Here, we identify non-genetic heterogeneity in the fidelity and timing of damage-induced G2 checkpoint enforcement in individual cells from the same population. Single-cell fluorescence imaging reveals that individual damaged cells experience varying durations of G2 arrest, and recover with varying levels of remaining checkpoint signal or DNA damage. A gating mechanism dependent on polo-like kinase-1 (PLK1) activity underlies this heterogeneity. PLK1 activity continually accumulates from initial levels in G2-arrested cells, at a rate inversely correlated to checkpoint activation, until it reaches a threshold allowing mitotic entry regardless of remaining checkpoint signal or DNA damage. Thus, homeostatic control of PLK1 by the dynamic opposition between checkpoint signalling and pro-mitotic activities heterogeneously enforces the G2 checkpoint in each individual cell, with implications for cancer pathogenesis and therapy.

Date: 2014
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DOI: 10.1038/ncomms5048

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