A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest

Abstract

SUMMARY Cellular responses to stimuli can evolve over time, resulting in distinct early and late phases in response to a single signal. DNA damage induces a complex response that is largely orchestrated by the transcription factor p53, whose dynamics influence whether a damaged cell will arrest and repair the damage or will initiate cell death. How p53 responses and cellular outcomes evolve in the presence of continuous DNA damage remains unknown. Here, we have found that a subset of cells switches from oscillating to sustained p53 dynamics several days after undergoing damage. The switch results from cell cycle progression in the presence of damaged DNA, which activates the caspase-2-PIDDosome, a complex that stabilizes p53 by inactivating its negative regulator MDM2. This work defines a molecular pathway that is activated if the canonical checkpoints fail to halt mitosis in the presence of damaged DNA.

The p53-caspase-2 axis in the cell cycle and DNA damage response

“…The cells with sustained p53 signaling showed chromosomal damage. The authors found that late phase p53 levels were reduced in irradiated PIDD1-deficient cells and in cells following caspase-2 inhibition 79 . Overall, their data suggest that PIDD1 and caspase-2 are required for cells that evade DNA damage-induced cell cycle arrest to switch from pulsating to sustained p53 signaling.…”

“…On the other hand, in response to UV-induced DNA damage that activates ATR, p53 is expressed as a broad pulse 78 . A study published in 2020 suggests that several days after ionizing radiation-induced DNA damage, some cells switch from oscillating to sustained p53 dynamics 79 . Using a Venus fluorescent reporter to monitor p53 levels in single cells, the authors found that following 10 Gy irradiation, 15–20% of cells exhibit stably increased p53 levels 79 .…”

“…A study published in 2020 suggests that several days after ionizing radiation-induced DNA damage, some cells switch from oscillating to sustained p53 dynamics 79 . Using a Venus fluorescent reporter to monitor p53 levels in single cells, the authors found that following 10 Gy irradiation, 15–20% of cells exhibit stably increased p53 levels 79 . Interestingly, the fraction of cells switching from pulsatile to sustained p53 levels was maximal at 5 Gy but reduced with increasing radiation dose of 10 or 20 Gy dose.…”

Oncogenic alterations in the p53 pathway abolish oscillatory competence

“…The parameter values we used are shown in Table S1. The justification for these values is as follows: α, β, γ : taken from Tsabar et al (2020); σ : taken from Mönke et al (2017), rescaled to agree with Tsabar et al (2020); κ: taken from Monke et al (2017); the parameters σ, ϵ, ϕ and δ form a group, all affecting Mdm2 dynamics. As a reality check, we verified that the chosen set of parameters produced oscillations in p53 protein levels with the characteristic period of 5-6 hours Lahav et al (2004), as well as oscillations in MDM2 transcript and Mdm2 protein levels that are consistent with experimental observations (Hanson et al, 2019).…”

At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

“…after cytokinesis failure [57], placing caspase-2 upstream of p53. Alternatively, PIDDosome-activated caspase-2 has been proposed to act as a fail-safe mechanism by initiating a stable p53 response in cells that escape cell cycle arrest following DNA damage [137]. Here, caspase-2 may act as an important safeguard of genome integrity downstream of p53.…”