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

Oncogene volume 32, pages 4721–4726 (2013)Cite this article

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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.

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Abbreviations

CDL4A:

Cullin4A (cul4A)-dependent ligase

E3:

E3 ubiquitin-protein ligase

E2:

E2 ubiquitin-conjugating enzymes

Cul:

cullin

DDB1:

DNA-binding protein 1

Met-Ub:

methylated ubiquitin.

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Acknowledgements

We are grateful to Michele Pagano for fruitful discussions on the topics covered in this article, and to Emre Sayan for providing the His-p73α recombinant protein. This work has been supported by the MIUR/PRIN grant 20078P7T3K_001 and AIRC grant 9202 awarded to FB, the Medical Research Council, UK; Odysseus and VIB, Belgium; grants from ‘Alleanza contro il Cancro’ (ACC12), MIUR/PRIN (20078P7T3K_001)/FIRB (RBIP06LCA9_0023, RBIP06LCA9_0C), AIRC (2008–2010_33–08) (grant number 5471), AIRC 5xmille (grant number 9979), MIUR/PRIN 2008MRLSNZ_004 to GM, the Ric Finalizzata 08-GIOV_RIC awarded to AP, the NIH grants 2R01CA098210, 5R01CA 118085 and Irma T Hirschl Career Scientist Award to PZ. This work was supported by funding from RFBS (10-04-01234), MCB RAS, Russian Federal grants 16.740.11.036 (to NB) and 11.G34.31.0069 (to GM). DRG was supported by grants from the US NIH.

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Author notes

  1. M Malatesta

    Present address: 10Current address: Biotech Research and Innovation Center (BRIC), Center for Epigenetics, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.,

Authors and Affiliations

  1. Department of Experimental Medicine and Surgery, University of Rome ‘Tor Vergata’, Rome, Italy

    M Malatesta, E M Memmi, G Melino & F Bernassola

  2. Department of Experimental Medicine and Surgery, IDI-IRCCS, Biochemistry Laboratory, University of Rome ‘Tor Vergata’, Rome, Italy

    A Peschiaroli

  3. Department of Biomedicine, Institute of Cellular Biology and Neurobiology, CNR, Rome, Italy

    A Peschiaroli

  4. Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and Weill Cornell Graduate School of Medical Sciences, New York, NY, USA

    J Zhang & P Zhou

  5. Medical Research Council, Toxicology Unit, University of Leicester, Leicester, UK

    A Antonov & G Melino

  6. Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA

    D R Green

  7. Saint-Petersburg State Institute of Technology, Saint-Petersburg, Russia

    N A Barlev, A V Garabadgiu & G Melino

  8. Department of Biochemistry, University of Leicester, Leicester, UK

    N A Barlev

  9. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

    F Bernassola

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Correspondence to G Melino or F Bernassola.

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Malatesta, M., Peschiaroli, A., Memmi, E. et al. The Cul4A–DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity. Oncogene 32, 4721–4726 (2013). https://doi.org/10.1038/onc.2012.463

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  • DOI: https://doi.org/10.1038/onc.2012.463

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