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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Liang, Hongqing 
Esposito, Alessandro  ORCID logo  https://orcid.org/0000-0002-5051-091X
De, Siddharth 
Ber, Suzan 
Collin, Philippe 

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.

Description

Keywords

Cell Cycle Proteins, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Damage, G2 Phase Cell Cycle Checkpoints, Genetic Heterogeneity, Homeostasis, Humans, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins, Time Factors, Polo-Like Kinase 1

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

5

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G1001521)
Medical Research Council (G1001522)
Medical Research Council (MC_UU_12022/1)
Wellcome Trust (092096/Z/10/Z)
MRC (MC_UU_12022/8)