title: The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity.
abstract: The Cullin4A (cul4A)-dependent ligase (CDL4A) E3 has been implicated in a variety of biological processes, including cell cycle progression and DNA damage response. Remarkably, CDL4A exerts its function through both proteolytic and non-proteolytic events. Here, we show that the p53 family member p73 is able to interact with the CDL4A complex through its direct binding to the receptor subunit DNA-binding protein 1 (DDB1). As a result, the CDL4A complex is able to monoubiquitylate p73. Modification of p73 by CDL4A-mediated ubiquitylation does not affect p73 protein stability, but negatively regulates p73-dependent transcriptional activity. Indeed, genetic or RNA interference-mediated depletion of DDB1 induces the expression of several p73 target genes in a p53-independent manner. In addition, by exploiting a bioinformatic approach, we found that elevated expression of Cul4A in human breast carcinomas is associated with repression of p73 target genes. In conclusion, our findings add a novel insight into the regulation of p73 by the CDL4A complex, through the inhibition of its transcriptional function.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Malatesta
authors.forename: A
authors.initials: A
authors.lastname: Peschiaroli
authors.forename: E M
authors.initials: EM
authors.lastname: Memmi
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Antonov
authors.forename: D R
authors.initials: DR
authors.lastname: Green
authors.forename: N A
authors.initials: NA
authors.lastname: Barlev
authors.forename: A V
authors.initials: AV
authors.lastname: Garabadgiu
authors.forename: P
authors.initials: P
authors.lastname: Zhou
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: F
authors.initials: F
authors.lastname: Bernassola
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D002277:Carcinoma / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology; D002460:Cell Line; D044842:Cullin Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D014158:Transcription, Genetic / Q000502:physiology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C479529:RBX1 protein, human; C495901:TP53 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins