Abstract
SummaryCell-autonomous changes in p53 expression govern the duration and outcome of cell-cycle arrest at the G2 checkpoint for DNA damage. Here, we report that mitogen-activated protein kinase (MAPK) signaling integrates extracellular cues with p53 dynamics to determine cell fate at the G2 checkpoint. Optogenetic tools and quantitative cell biochemistry reveal transient oscillations in MAPK activity dependent on ataxia-telangiectasia-mutated kinase after DNA damage. MAPK inhibition alters p53 dynamics and p53-dependent gene expression after checkpoint enforcement, prolonging G2 arrest. In contrast, sustained MAPK signaling induces the phosphorylation of CDC25C, and consequently, the accumulation of pro-mitotic kinases, thereby relaxing checkpoint stringency and permitting cells to evade prolonged G2 arrest and senescence induction. We propose a model in which this MAPK-mediated mechanism integrates extracellular cues with cell-autonomous p53-mediated signals, to safeguard genomic integrity during tissue proliferation. Early steps in oncogene-driven carcinogenesis may imbalance this tumor-suppressive mechanism to trigger genome instability.
Highlights
To maintain tissue function and homeostasis, mammalian cells respond to extracellular cues via signal transduction networks (STNs) that relay information from membrane receptors to the cell nucleus to influence cell fate decisions
Recent evidence suggests that cell fate decisions executed during processes that are seemingly cell autonomous may be regulated by STNs that respond to extracellular cues
We reveal the previously unnoticed pulsatile activation of mitogen-activated protein kinase (MAPK) signaling after DNA damage and show how it intersects with the cell-autonomous control of p53 dynamics
Summary
To maintain tissue function and homeostasis, mammalian cells respond to extracellular cues via signal transduction networks (STNs) that relay information from membrane receptors to the cell nucleus to influence cell fate decisions. Pulses of p53 expression induced by DSBs mediate cell-cycle arrest, whereas sustained p53 activation instead triggers terminal cell fates, such as apoptosis or senescence (Batchelor et al, 2011; Purvis et al, 2012) These alternate fates are mediated through the differential transcriptional activation of downstream target genes that are dependent on the pattern (transient or periodic versus sustained) of upstream activators (Purvis et al, 2012; Loewer et al, 2010; Toettcher et al, 2009; Santos et al, 2007; Shankaran et al, 2009; Yamamoto et al, 2006). It remains unclear mechanistically how MAPK dynamics exerts its influence, in the G2 phase of the cell cycle and in the presence of DNA damage
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