BEND3 Represses rDNA Transcription by Stabilizing a NoRC Component via USP21 Deubiquitinase

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8338-43. doi: 10.1073/pnas.1424705112. Epub 2015 Jun 22.

Abstract

Ribosome biogenesis dictates the translational capacity of cells. Several mechanisms establish and maintain transcriptional output from eukaryotic ribosomal DNA (rDNA) loci. rDNA silencing is one such mechanism that ensures the inactivity and hence the maintenance of a silenced state of a subset of rRNA gene copies. Whereas oncogenic agents stimulate rRNA gene transcription, tumor suppressors decrease rRNA gene transcription. We demonstrate in mammalian cells that BANP, E5R, and Nac1 (BEN) domain 3 (BEND3), a quadruple BEN domain-containing protein, localizes in nucleoli and binds to ribosomal RNA gene promoters to help repress rRNA genes. Loss of BEND3 increases histone H3K4 trimethylation and, correspondingly, decreases rDNA promoter DNA methylation, consistent with a role for BEND3 in rDNA silencing. BEND3 associates with the nucleolar-remodeling complex (NoRC), and SUMOylated BEND3 stabilizes NoRC component TTF-1-interacting protein 5 via association with ubiquitin specific protease 21 (USP21) debiquitinase. Our results provide mechanistic insights into how the novel rDNA transcription repressor BEND3 acts together with NoRC to actively coordinate the establishment of rDNA silencing.

Keywords: BEND3; NoRC; Tip5; rDNA; transcription repression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Nucleolus / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA, Ribosomal / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Histones / metabolism
  • Humans
  • Lysine / metabolism
  • Methylation
  • Microscopy, Fluorescence
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sumoylation
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism

Substances

  • BAZ2A protein, human
  • BEND3 protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA, Ribosomal
  • Histones
  • Repressor Proteins
  • USP21 protein, human
  • Ubiquitin Thiolesterase
  • Lysine