TRIM24 Is a p53-Induced E3-Ubiquitin Ligase That Undergoes ATM-Mediated Phosphorylation and Autodegradation during DNA Damage

Abstract

Tumor suppressor p53 protects cells from genomic insults and is a target of mutation in more than 50% of human cancers. Stress-mediated modification and increased stability of p53 promote p53 interaction with chromatin, which results in transcription of target genes that are critical for the maintenance of genomic integrity. We recently discovered that TRIM24, an E3-ubiquitin ligase, ubiquitinates and promotes proteasome-mediated degradation of p53. Here, we show that TRIM24 is destabilized by ATM-mediated phosphorylation of TRIM24S768 in response to DNA damage, which disrupts TRIM24-p53 interactions and promotes the degradation of TRIM24. Transcription of TRIM24 is directly induced by damage-activated p53, which binds p53 response elements and activates expression of TRIM24. Newly synthesized TRIM24 interacts with phosphorylated p53 to target it for degradation and termination of the DNA damage response. These studies indicate that TRIM24, like MDM2, controls p53 levels in an autoregulatory feedback loop. However, unlike MDM2, TRIM24 also targets activated p53 to terminate p53-regulated response to DNA damage. Tumor suppressor p53 maintains the genomic integrity of a cell in response to a variety of cellular stresses, including DNA damage, oncogenic stress, telomere dysfunction, and hypoxia (1-3). When exposed to stress stimuli, p53 acts as a central relay to determine how the cells respond, whether by apoptosis, cell cycle arrest, senescence, DNA repair, shifts in cell metabolism, or autophagy (4). Multiple signaling pathways converge on p53 to control its protein stability and activities, primarily by posttranslational modifications (PTMs) of p53 at specific amino acid residues (5-7). One of the major pathways that negatively regulate p53 protein stability is the ubiquitin-proteasome system, which adds polymerized chains of ubiquitin to p53 to target it for degradation (8, 9). The importance of this mechanism for cellular homeostasis is illustrated by p53-dependent embryonic lethality with germ line deletion of murine Mdm2 (10), the first identified E3-ubiquitin ligase for p53 (11-13). However, a striking observation is that p53 degradation occurs even in Mdm2-deficient mouse tissues during cellular recovery after DNA damage (14). In addition, a recent report suggests that the p53-MDM2 feedback loop is dispensable for p53 stability after DNA damage in vivo (15). This suggested that a negative-feedback loop, which controls p53 protein levels, remains operable even in the absence of Mdm2. A collection of more than 15 E3-ubiquitin ligases that directly regulate p53 stability, including Pirh2, COP1, ARF-BP1 and others, are now known (16-18). These ligases stimulate p53 ubiquitination and degradation by directly modifying lysine residues, but their specific or redundant roles in regulation of p53 and how they themselves are regulated remain largely unknown.We found that TRIM24 was an E3-ubiquitin ligase that negatively regulates p53 by directly targeting p53 for ubiquitination via a conserved RING domain (19). TRI...

TRIM24 promotes the aggression of gastric cancer via the Wnt/β-catenin signaling pathway

“…TRIM24 binds to the phosphoinositide 3-kinase (PI3K) promoter to activate PI3K/Akt signaling, leading to the upregulation of downstream targets, including nuclear factor-κB, and the induction of cell proliferation and chemoresistance (27). In addition, TRIM24 has been reported to interact with p53 and control the level of phosphorylated p53 in an autoregulatory feedback loop (31). The previous studies, demonstrated that TRIM24 can modify cell proliferation, migration, invasion and apoptosis.…”

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

“…Mdm2 is the main E3 ubiquitin ligase that targets p53 for proteasomal degradation and inhibits its function as a transcription factor (for a review on Mdm2 and p53, see Wade et al, 2013), whereas Wip1 dephosphorylates both p53 and Mdm2 to promote p53 degradation (Lu et al, 2005;Lu et al, 2007). Recently, TRIM24 was identified as an additional p53-induced ubiquitin ligase that preferentially targets phosphorylated variants of p53 for degradation (Jain et al, 2014). As a result, p53 levels oscillate in response to DNA damage and altering the oscillatory pattern of p53 results in distinct cell fate outcomes (Batchelor et al, 2008;Lahav et al, 2004;Purvis et al, 2012).…”

Limiting the power of p53 through the ubiquitin proteasome pathway

“…TRIM24 is overexpressed in breast cancer and other human tumors (Tsai et al 2010;Chambon et al 2011). A recent study provides evidence that Trim24 prefers phosphorylated p53 for targeting (Jain et al 2014). This would imply that Trim24 is responsible for degrading active p53.…”