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PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth

Weijia Cai1, Liya Su1, Lili Liao1,2

  • 1Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Nature Communications
|December 22, 2019
PubMed

Insights

The study identifies Polybromo and Ring Finger And CCCH-Type Zinc Finger Domains 1 (PBRM1) as a reader for p53 acetylation, crucial for its tumor-suppressive function in kidney cancer.

Area of Science:

  • Molecular Biology
  • Oncology
  • Epigenetics

Background:

  • p53 acetylation is vital for its tumor suppressor activity, but the proteins that read this modification were unknown.
  • Polybromo and Ring Finger And CCCH-Type Zinc Finger Domains 1 (PBRM1) is frequently mutated in kidney cancer.
  • Understanding p53 acetylation readers is key to deciphering tumor suppression mechanisms.

Purpose of the Study:

  • To identify the reader protein(s) for p53 acetylation.
  • To investigate the role of PBRM1 in recognizing p53 acetylation and its impact on tumor suppression.
  • To elucidate the mechanism linking p53, PBRM1, and kidney cancer.

Main Methods:

  • Utilized biochemical assays to identify PBRM1 as a reader of p53 acetylation at lysine 382 (K382Ac).
  • Investigated the function of PBRM1's bromodomain 4 (BD4) in p53 K382Ac recognition.
  • Assessed the impact of PBRM1 mutations on p53 transcriptional activity and tumor suppressor function.
  • Correlated PBRM1 and p21 expression in human kidney cancer samples.

Main Results:

  • PBRM1 directly binds to acetylated p53 (p53 K382Ac) via its bromodomain 4 (BD4).
  • Mutations in PBRM1 BD4 impair p53 K382Ac recognition, reduce p53 binding to target gene promoters (e.g., CDKN1A/p21), and compromise p53 transcriptional activity.
  • PBRM1 mutants are defective in tumor suppression, and PBRM1 and p21 expression levels correlate in kidney cancer patients.

Conclusions:

  • PBRM1 acts as a critical reader of p53 acetylation, linking p53 function to the SWI/SNF chromatin remodeling complex.
  • This interaction is essential for p53's tumor suppressive role in kidney cancer.
  • Defects in PBRM1's ability to read p53 acetylation contribute to kidney tumorigenesis.

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