title: Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing.
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.
authors.affiliation: 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.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Liang
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Siddharth
authors.initials: S
authors.lastname: De
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Suzan
authors.initials: S
authors.lastname: Ber
authors.affiliation: Gurdon Institute, Department of Zoology, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Collin
authors.affiliation: 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.
authors.forename: Uttam
authors.initials: U
authors.lastname: Surana
authors.affiliation: Medical Research Council Cancer Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D059565:G2 Phase Cell Cycle Checkpoints; D018740:Genetic Heterogeneity; D006706:Homeostasis; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013997:Time Factors; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1