title: 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.
authors.forename: Abhinav K
authors.initials: AK
authors.lastname: Jain
authors.forename: Kendra
authors.initials: K
authors.lastname: Allton
authors.forename: Aundrietta D
authors.initials: AD
authors.lastname: Duncan
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Barton
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; C495901:TP53 protein, human; C555317:TRIM24 protein, human; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D012694:Serine; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins