PT  - JOURNAL ARTICLE
AU  - Hui Xiao Chao
AU  - Cere E. Poovey
AU  - Ashley A. Privette
AU  - Gavin D. Grant
AU  - Jeanette G. Cook
AU  - Jeremy E. Purvis
TI  - DNA damage checkpoint dynamics drive cell cycle phase transitions
AID  - 10.1101/137307
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 137307
4099  - http://biorxiv.org/content/early/2017/05/12/137307.short
4100  - http://biorxiv.org/content/early/2017/05/12/137307.full
AB  - DNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. The prevailing paradigm of DNA damage checkpoints is that they halt cell cycle progression until the damage is repaired, allowing cells time to recover from damage before resuming normal proliferation. Here, we challenge this model by observing cell cycle phase transitions in individual proliferating cells responding to acute DNA damage under live imaging conditions. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the length of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. In contrast, cell cycle progression in S phase is significantly less sensitive to DNA damage. Instead of exhibiting a complete halt to cell cycle progression, our results are consistent with high DNA damage doses causing a decreased rate of progression. These phase-specific differences in DNA damage checkpoint dynamics lead to corresponding differences in the proportions of irreversibly arrested cells. Thus, the precise timing of DNA damage determines the sensitivity, rate of progression, and functional outcome of DNA damage checkpoints. These findings both explain and inform our understanding of cell fate decisions after treatment with common cancer therapeutics such as genotoxins or spindle poisons, which often target cells in a specific cell cycle phase.