p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

Abstract

The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cellcycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

“…APC is a multicomponent ubiquitin ligase well known to regulate the cell cycle. Several recent studies have indicated that APC is activated upon DNA damage in an ATM-dependent as well as an ATMindependent manner (55)(56)(57). Although it is not clear whether NF-B was involved in the DDR-induced APC activation in these studies, it is reasonable to speculate that E1-dependent activation of DDR induces activation of APC, possibly through NF-B.…”

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

“…This initiates the destruction of cyclin B1 and a decrease in Cdk activity, which is required to allow Cdh1-dependent activation of the APC/C during the late stages of mitosis and throughout G1. DNA damage in G2 can activate APC/C Cdh1 , which is essential for a persistent G2 arrest and requires p53-and p21-dependent Cdk inhibition (Bassermann et al, 2008;Lee et al, 2009;Sudo et al, 2001;Wiebusch and Hagemeier, 2010). Premature activation of the APC/C Cdh1 in G2 by DNA damage targets many proteins required for mitotic entry for destruction, including cyclin A, cyclin B1 and Plk1, thus preventing recovery from a G2 arrest (Fig.…”

“…Premature activation of the APC/C Cdh1 in G2 by DNA damage targets many proteins required for mitotic entry for destruction, including cyclin A, cyclin B1 and Plk1, thus preventing recovery from a G2 arrest (Fig. 4A) (Johmura et al, 2014;Krenning et al, 2014;Lee et al, 2009;Lindqvist et al, 2009b;Wiebusch and Hagemeier, 2010). The resulting cells that have a G2 DNA content but lack G2-specific protein expression are committed to senescence (Johmura et al, 2014;Ye et al, 2013).…”

Senescence from G2 arrest, revisited

“…2). However, subsequent work in several laboratories provided evidence that this is also due to protein degradation triggered by anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 [74][75][76] (Fig. 2).…”

“…93 Moreover, stable G2 arrest induced by ionizing radiation (IR) was associated with p53/p21-dependent premature APC/C Cdh1 activation and degradation of mitotic cyclins, consistent with previous observations. [74][75][76] However, unlike p53-mediated mitotic bypass, APC/C Cdh1 activation alone does not appear to be sufficient to induce senescence, that additionally requires repression of mitotic regulators by pRb family pocket proteins (Fig. 2).…”