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Updated: Apr 29, 2026
Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
Published on: June 9, 2017
TRIM24 is a p53-induced E3-ubiquitin ligase that undergoes ATM-mediated phosphorylation and autodegradation during
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.
Insights
The tumor suppressor p53 is regulated by TRIM24, an E3-ubiquitin ligase. TRIM24 targets p53 for degradation, controlling the DNA damage response and maintaining genomic integrity.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Biology
Background:
- The p53 tumor suppressor is crucial for genomic integrity and is frequently mutated in human cancers.
- p53 stability and chromatin interaction are regulated by stress-mediated modifications, leading to the transcription of DNA repair genes.
- TRIM24, an E3-ubiquitin ligase, was previously identified to ubiquitinate and degrade p53.
Purpose of the Study:
- To elucidate the regulatory mechanism of TRIM24 in response to DNA damage.
- To investigate the interplay between TRIM24, p53, and the DNA damage response pathway.
- To understand how TRIM24 controls p53 levels and terminates the DNA damage response.
Main Methods:
- Investigated TRIM24 phosphorylation by ATM in response to DNA damage.
- Analyzed the effect of TRIM24 phosphorylation on TRIM24-p53 interactions and TRIM24 degradation.
- Studied the transcriptional regulation of TRIM24 by p53 using p53 response elements.
- Examined the interaction of newly synthesized TRIM24 with phosphorylated p53.
Main Results:
- ATM-mediated phosphorylation of TRIM24 at Ser768 destabilizes TRIM24 in response to DNA damage.
- TRIM24 destabilization disrupts TRIM24-p53 interaction and promotes TRIM24 degradation.
- Damage-activated p53 directly induces TRIM24 transcription by binding to p53 response elements.
- Newly synthesized TRIM24 targets phosphorylated p53 for degradation, terminating the DNA damage response.
Conclusions:
- TRIM24 functions in an autoregulatory feedback loop with p53, similar to MDM2, to control p53 levels.
- TRIM24 uniquely targets activated p53 for degradation, thereby terminating the p53-regulated DNA damage response.
- TRIM24 plays a critical role in regulating the duration and termination of the DNA damage response, impacting genomic stability and cancer development.
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