Transcriptional Activation of Pericentromeric Satellite Repeats and Disruption of Centromeric Clustering upon Proteasome Inhibition

PLoS One. 2016 Nov 2;11(11):e0165873. doi: 10.1371/journal.pone.0165873. eCollection 2016.

Abstract

Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres.

MeSH terms

  • Acetylation
  • Animals
  • Centromere / chemistry*
  • Centromere / drug effects
  • Centromere / genetics
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromosomal Instability
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA, Satellite / drug effects
  • DNA, Satellite / genetics*
  • Histones / metabolism
  • In Situ Hybridization, Fluorescence
  • Leupeptins / pharmacology*
  • Mice
  • NIH 3T3 Cells
  • Proteasome Endopeptidase Complex / metabolism*
  • Transcription, Genetic / drug effects

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DNA, Satellite
  • Histones
  • Leupeptins
  • heterochromatin-specific nonhistone chromosomal protein HP-1
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde