USP7 Enforces Heterochromatinization of p53 Target Promoters by Protecting SUV39H1 from MDM2-Mediated Degradation

Cell Rep. 2016 Mar 22;14(11):2528-37. doi: 10.1016/j.celrep.2016.02.049. Epub 2016 Mar 10.

Abstract

The H3K9me3 repressive histone conformation of p53 target promoters is abrogated in response to p53 activation by MDM2-mediated SUV39H1 degradation. Here, we present evidence that the USP7 deubiquitinase protects SUV39H1 from MDM2-mediated ubiquitination in the absence of p53 stimulus. USP7 occupies p53 target promoters in unstressed conditions, a process that is abrogated with p53 activation associated with loss of the H3K9me3 mark on these same promoters. Mechanistically, USP7 forms a trimeric complex with MDM2 and SUV39H1, independent of DNA, and modulates MDM2-dependent SUV39H1 ubiquitination. Furthermore, we show that this protective function of USP7 on SUV39H1 is independent of p53. Finally, USP7 blocking cooperates with p53 in inducing apoptosis by enhancing p53 promoter occupancy and dependent transactivation of target genes. These results uncover a layer of the p53 transcriptional program mediated by USP7, which restrains relaxation of local chromatin conformation at p53 target promoters.

Keywords: H3K9me3; MDM2; SUV39H1; USP7; p53.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Phytogenic / toxicity
  • Apoptosis / drug effects
  • Blotting, Western
  • DNA / metabolism
  • Etoposide / toxicity
  • HCT116 Cells
  • Heterochromatin / metabolism
  • Histones / metabolism
  • Humans
  • Immunoprecipitation
  • Methyltransferases / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Stability
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin Thiolesterase / antagonists & inhibitors
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination

Substances

  • Antineoplastic Agents, Phytogenic
  • Heterochromatin
  • Histones
  • RNA, Small Interfering
  • Repressor Proteins
  • Tumor Suppressor Protein p53
  • Etoposide
  • DNA
  • SUV39H1 protein, human
  • Methyltransferases
  • Proto-Oncogene Proteins c-mdm2
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7