Abstract
Regulation of p53 by ubiquitination and deubiquitination is important for its function. In this study, we demonstrate that USP24 deubiquitinates p53 in human cells. Functional USP24 is required for p53 stabilization, and p53 destabilization in USP24-depleted cells can be corrected by the forced expression of USP24. We show that USP24 depletion renders cells resistant to apoptosis after UV irradiation, consistent with the requirement of USP24 for p53 stabilization and PUMA activation invivo. Additionally, purified USP24 protein is able to cleave ubiquitinated p53 invitro. Importantly, cells with USP24 depletion exhibited significantly elevated mutation rates at the endogenous HPRT locus, implying an important role for USP24 in maintaining genome stability. Our data reveal that the USP24 deubiquitinase regulates the DNA damage response by directly targeting the p53 tumor suppressor.
Highlights
The tumor suppressor p53 functions as a stress sensor to protect genome integrity and, reasonably, is mutated in more than half of human cancers (Lane and Levine, 2010; Vogelstein et al, 2000). p53 integrates multiple stress signals into a series of diverse antiproliferative responses, one of which is to activate apoptosis when cells are under stress
Mdm2 acts as the major E3ubiquitin ligase targeting p53 for degradation (Haupt et al, 1997; Honda et al, 1997; Kubbutat et al, 1997). p53 degradation is inhibited after cellular stress, allowing activated p53 to regulate a variety of cellular functions, including DNA repair, cell cycle progression and apoptosis (Lee and Gu, 2010; Marine and Lozano, 2010)
Our group previously reported that ubiquitinated DDB2 can be targeted by USP24 (Zhang et al, 2012), and in this study, we demonstrate that USP24 is a p53 deubiquitinase, required for p53 stabilization in unstressed cells, as well as for p53 stabilization and p53 upregulated modulator of apoptosis (PUMA) activation after DNA damage
Summary
The tumor suppressor p53 functions as a stress sensor to protect genome integrity and, reasonably, is mutated in more than half of human cancers (Lane and Levine, 2010; Vogelstein et al, 2000). p53 integrates multiple stress signals into a series of diverse antiproliferative responses, one of which is to activate apoptosis when cells are under stress. P53 integrates multiple stress signals into a series of diverse antiproliferative responses, one of which is to activate apoptosis when cells are under stress. Disruption of p53 function process can promote tumor progression and chemoresistance (Muller and Vousden, 2013; Wade et al, 2013). Posttranslational modifications are known to regulate p53 stability, activity and localization; in particular the ubiquitination and deubiquitination pathways have emerged as dynamic and coordinated processes regulating p53 functions. As a very short-lived protein in the cell, p53 is constantly degraded by the ubiquitin-proteasome pathway. P53 degradation is inhibited after cellular stress, allowing activated p53 to regulate a variety of cellular functions, including DNA repair, cell cycle progression and apoptosis (Lee and Gu, 2010; Marine and Lozano, 2010) Mdm acts as the major E3ubiquitin ligase targeting p53 for degradation (Haupt et al, 1997; Honda et al, 1997; Kubbutat et al, 1997). p53 degradation is inhibited after cellular stress, allowing activated p53 to regulate a variety of cellular functions, including DNA repair, cell cycle progression and apoptosis (Lee and Gu, 2010; Marine and Lozano, 2010)
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