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

• DOI: 10.1038/ncomms5048
• Publication Date: 2014-06-04T11:44:49Z
• Authors: Hongqing Liang; Alessandro Esposito; Siddharth De; Suzan Ber; Philippe Collin; Uttam Surana; Ashok R. Venkitar...
• Keywords: 0303 health sciences; Time Factors; Cell Cycle Proteins; Protein Serine-Threonine Kinases; Article; G2 Phase Cell Cycle Checkpoints; Polo-Like Kinase 1; Genetic Heterogeneity; 03 medical and health sciences; Cell Line, Tumor; Proto-Oncogene Proteins; Homeostasis; Humans; DNA Breaks, Double-Stranded; DNA Damage

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.