TY - JOUR
T1 - The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity
AU - Malatesta, M.
AU - Peschiaroli, A.
AU - Memmi, E. M.
AU - Zhang, J.
AU - Antonov, A.
AU - Green, D. R.
AU - Barlev, N. A.
AU - Garabadgiu, A. V.
AU - Zhou, P.
AU - Melino, G.
AU - Bernassola, F.
PY - 2013/9/26
Y1 - 2013/9/26
N2 - 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.
AB - 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.
KW - apoptosis
KW - p73
KW - protein ubiquitylation
UR - http://www.scopus.com/inward/record.url?scp=84884902595&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884902595&partnerID=8YFLogxK
U2 - 10.1038/onc.2012.463
DO - 10.1038/onc.2012.463
M3 - Article
C2 - 23085759
AN - SCOPUS:84884902595
VL - 32
SP - 4721
EP - 4726
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 39
ER -