The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity

M. Malatesta, A. Peschiaroli, E. M. Memmi, J. Zhang, A. Antonov, D. R. Green, N. A. Barlev, A. V. Garabadgiu, P. Zhou, G. Melino, F. Bernassola

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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.

Original languageEnglish
Pages (from-to)4721-4726
Number of pages6
JournalOncogene
Volume32
Issue number39
DOIs
Publication statusPublished - Sep 26 2013

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Keywords

  • apoptosis
  • p73
  • protein ubiquitylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Malatesta, M., Peschiaroli, A., Memmi, E. M., Zhang, J., Antonov, A., Green, D. R., Barlev, N. A., Garabadgiu, A. V., Zhou, P., Melino, G., & Bernassola, F. (2013). The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity. Oncogene, 32(39), 4721-4726. https://doi.org/10.1038/onc.2012.463