Abstract
p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes.
Highlights
P53 acetylation is indispensable for its transcriptional activity and tumor suppressive function
Various posttranslational modifications occur on p53, and acetylation on eight key lysine residues was found to be critical for modulation of its transcriptional activity2. p53 acetylation can be divided into two groups: acetylation on two lysine residues in p53′s DNAbinding domain (K120 and K164), which directly affects its binding to DNA2–4 and acetylation on six lysine residues in p53’s C-terminal domain (CTD) (K370, K372, K373, K381, K382, and K386), which regulates its transcriptional activity through interactions with other proteins, known as acetylation ‘readers’5–11. p53 acetylation ‘writers’ such as histone acetyltransferases and ‘erasers’ such as histone deacetylases and sirtuins are well described[1], but the identities and functions of p53 acetylation ‘readers’ remain unclear
In this report we found that Polybromo-1 gene (PBRM1) and p53 physically associate
Summary
P53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. CBP and SET fail to fully account for the biological activity of p53′s acetylated CTD, suggesting that other reader(s) exists. In agreement with it being a pivotal TSG, around half of human tumors harbor mutations in TP53. Clear cell Renal Cell Carcinoma (ccRCC), the most common subtype of kidney cancer, seems to be an exception: only a small subset of tumors harbor mutations in TP53 (~3%)[12]. This suggests the possibility that p53 tumor suppressor function may be compromised by mutations of other genes in ccRCC tumors. We find that BD4 of PBRM1 is critical for recognition of K382Ac on p53 and this is critical for PBRM1′s tumor suppressor function
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