Orchestration of DNA Damage Checkpoint Dynamics Across the Human Cell Cycle

Overview

Journal Cell Syst

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Nov 6

PMID 29102360

Citations 79

Authors

Hui Xiao Chao

Cere E Poovey

Ashley A Privette

Gavin D Grant

Hui Yan Chao

Jeanette G Cook

Jeremy E Purvis

Affiliations

Soon will be listed here.

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.

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