Abstract
Tetramerization of p53 is crucial to exert its biological activity, and nucleolar disruption is sufficient to activate p53. We previously demonstrated that nucleolar stress induces translocation of the nucleolar protein MYBBP1A from the nucleolus to the nucleoplasm and enhances p53 activity. However, whether and how MYBBP1A regulates p53 tetramerization in response to nucleolar stress remain unclear. In this study, we demonstrated that MYBBP1A enhances p53 tetramerization, followed by acetylation under nucleolar stress. We found that MYBBP1A has two regions that directly bind to lysine residues of the p53 C-terminal regulatory domain. MYBBP1A formed a self-assembled complex that provided a molecular platform for p53 tetramerization and enhanced p300-mediated acetylation of the p53 tetramer. Moreover, our results show that MYBBP1A functions to enhance p53 tetramerization that is necessary for p53 activation, followed by cell death with actinomycin D treatment. Thus, we suggest that MYBBP1A plays a pivotal role in the cellular stress response.
Highlights
Nucleolar disruption is involved in cellular stress response and is sufficient for p53 activation. p53 tetramerization is crucial to exert its activity
We previously demonstrated that nucleolar stress induces translocation of the nucleolar protein Myb-binding protein 1A (MYBBP1A) from the nucleolus to the nucleoplasm and enhances p53 activity
Our results show that MYBBP1A functions to enhance p53 tetramerization that is necessary for p53 activation, followed by cell death with actinomycin D treatment
Summary
Nucleolar disruption is involved in cellular stress response and is sufficient for p53 activation. p53 tetramerization is crucial to exert its activity. We demonstrated that MYBBP1A enhances p53 tetramerization, followed by acetylation under nucleolar stress. Activation of p53 in response to DNA damage begins with tetramerization of p53, which provides appropriate binding sites for p300 and leads to binding of p300 and subsequent acetylation of p53 C-terminal lysine residues. Recent studies on the cellular response to nucleolar stress have demonstrated that several nucleolar proteins are involved in activating p53. Ribosomal proteins such as RPS7, RPL5, RPL11, and RPL23 directly bind to HDM2 and inhibit HDM2-mediated p53 ubiquitination [45,46,47,48,49,50,51]. We suggest that MYBBP1A plays a pivotal role in the cellular stress response
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