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Cell Syst. 2017 Nov 22;5(5):445-459.e5. doi: 10.1016/j.cels.2017.09.015. Epub 2017 Oct 25.

Orchestration of DNA Damage Checkpoint Dynamics across the Human Cell Cycle.

Author information

1
Department of Genetics, University of North Carolina, Chapel Hill, Genetic Medicine Building 5061, CB#7264, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA; Curriculum for Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA.
2
Department of Genetics, University of North Carolina, Chapel Hill, Genetic Medicine Building 5061, CB#7264, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA.
3
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA.
4
Department of Genetics, University of North Carolina, Chapel Hill, Genetic Medicine Building 5061, CB#7264, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA; Curriculum for Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, 120 Mason Farm Road, Chapel Hill, NC 27599-7264, USA. Electronic address: jeremy_purvis@med.unc.edu.

Abstract

Although molecular mechanisms that prompt cell-cycle arrest in response to DNA damage have been elucidated, the systems-level properties of DNA damage checkpoints are not understood. Here, using time-lapse microscopy and simulations that model the cell cycle as a series of Poisson processes, we characterize DNA damage checkpoints in individual, asynchronously proliferating cells. We demonstrate that, within early G1 and G2, checkpoints are stringent: DNA damage triggers an abrupt, all-or-none cell-cycle arrest. The duration of this arrest correlates with the severity of DNA damage. After the cell passes commitment points within G1 and G2, checkpoint stringency is relaxed. By contrast, all of S phase is comparatively insensitive to DNA damage. This checkpoint is graded: instead of halting the cell cycle, increasing DNA damage leads to slower S phase progression. In sum, we show that a cell's response to DNA damage depends on its exact cell-cycle position and that checkpoints are phase-dependent, stringent or relaxed, and graded or all-or-none.

KEYWORDS:

DNA damage; cell-cycle checkpoints; computational modeling; live-cell imaging; single-cell dynamics

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