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  current news   Press   selected story    
     
  27 June 2014  
  Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing
 
 



Authors
Liang H1,3,4, Esposito A1, De S2, Ber S1, Collin P2, Surana U3,4, Venkitaraman AR1

1   Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK
2   Gurdon Institute, Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK
3   Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Biopolis Drive,      Biopolis Way, Singapore 138673
4   Bioprocessing Technology Institute, Agency for Science Technology and Research, Biopolis Way,      Singapore 138668

Published in Nat Commun on 4 June 2014.

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.

Figure Legend: Hypothetical model for homeostatic control of the G2 checkpoint in human cells. Key features of a hypothetical model for homeostatic control of the G2 checkpoint are schematically illustrated. During G2 arrest induced by DNA damage, cells continue to accumulate PLK1 activity (left) until its cumulative value reaches a threshold (yellow dotted line, top) that gates mitotic entry. Note that G2 arrested cells may have different initial levels of existing PLK1 activity (compare cells at left). The rate of increase in PLK1 activity (black lines, centre) in any given cell is negatively correlated to the level of DNA damage (red dots in cell nuclei) but positively correlated to existing level of PLK1 activity. The integration of these parameters determines the duration of G2 arrest, and the amount of DNA damage or checkpoint activation signal in mitotic cells that have recovered from G2 arrest (lines at the top). The comparison between Cells 1 and 3 illustrates the effect of levels of initial PLK1 activity on the duration of G2 arrest. Thus, Cell 1, which arrests with a high level of initial PLK1 activity, exhibits a shorter duration of G2 arrest despite a high level of DNA damage. In contrast, Cell 3, which arrests with a low level of initial PLK1 activity, exhibits a longer duration of G2 arrest despite bearing the same level of DNA damage as Cell 1, and enters mitosis with a lower number of damage foci owing to the increased time for G2 repair. The comparison between Cells 2 and 3 illustrates the effect of different amounts of DNA damage on the rate of accumulation of PLK1 activity and the duration of mitotic arrest. Thus, Cells 2 and 3 arrest with similar low levels of PLK1 activity. However, the rate of accumulation of PLK1 activity is higher in Cell 2 than in Cell 3 because it bears a lower amount of DNA damage, and so Cell 2 recovers from the G2 checkpoint and enters mitosis more quickly than Cell 3, and with a different amount of residual checkpoint signal or underlying DNA damage.

For more information on Uttam SURANA’s laboratory, click here.