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.

CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

“…However, upon UV-irradiation CRL4 CDT2 affinity for p53 attenuates, leading to its stabilization [10,102]. CUL4A also brings about inactivation of transcriptional function of p73, a structural and functional homologue of p53 [103]. This repression was found to correlate with overexpression of CUL4A in human breast carcinoma [103].…”

“…CUL4A also brings about inactivation of transcriptional function of p73, a structural and functional homologue of p53 [103]. This repression was found to correlate with overexpression of CUL4A in human breast carcinoma [103]. Additionally, CUL4A targets p150/Sal2 for degradation when cells transit from quiescence to mitotic state [104].…”

Targetome profiling and functional genetics implicate miR-618 in lymphomagenesis

“…22 Abrogation of CUL4A expression has been shown to augment DNA damage response, a function that may be attributable to the ubiquitination and subsequent proteasomal degradation of the tumor suppressors p53 and p73. 23,24 Interestingly, CUL4A also represses the tumor suppressor and potent reactive oxygen scavenger SOD2, 25 which has been implicated in risk for B-cell NHL and FL survival. 26,27 More intriguing is the identification of HDAC3 among captured "targets."…”

Regulation of the DNA damage response by ubiquitin conjugation

“…Furthermore, p63 and p73 protein stability are directly regulated by the ubiquitin ligase ITCH (Rossi et al, 2005, 2006). p73 is a substrate of the Cul4A-DDB1 Ub ligase complex which monoubiquitylates p73 thereby reducing its transcriptional activity without affecting its turnover (Malatesta et al, 2013). MDM2 also binds p73 without supporting its degradation (Balint et al, 1999).…”