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Nat Commun. 2014 Jun 4;5:4048. doi: 10.1038/ncomms5048.

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

Author information

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

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.

PMID:
24893992
PMCID:
PMC4059941
DOI:
10.1038/ncomms5048
[Indexed for MEDLINE]
Free PMC Article

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