Basis of the H2AK119 specificity of the Polycomb repressive deubiquitinase

Nature. 2023 Apr;616(7955):176-182. doi: 10.1038/s41586-023-05841-y. Epub 2023 Mar 29.

Abstract

Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification1-3. The Polycomb repressive deubiquitinase (PR-DUB) complex removes the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2AK119ub1) on the nucleosome4, counteracting the ubiquitin E3 ligase activity of Polycomb repressive complex 1 (PRC1)5 to facilitate the correct silencing of genes by Polycomb proteins and safeguard active genes from inadvertent silencing by PRC1 (refs. 6-9). The intricate biological function of PR-DUB requires accurate targeting of H2AK119ub1, but PR-DUB can deubiquitinate monoubiquitinated free histones and peptide substrates indiscriminately; the basis for its exquisite nucleosome-dependent substrate specificity therefore remains unclear. Here we report the cryo-electron microscopy structure of human PR-DUB, composed of BAP1 and ASXL1, in complex with the chromatosome. We find that ASXL1 directs the binding of the positively charged C-terminal extension of BAP1 to nucleosomal DNA and histones H3-H4 near the dyad, an addition to its role in forming the ubiquitin-binding cleft. Furthermore, a conserved loop segment of the catalytic domain of BAP1 is situated near the H2A-H2B acidic patch. This distinct nucleosome-binding mode displaces the C-terminal tail of H2A from the nucleosome surface, and endows PR-DUB with the specificity for H2AK119ub1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Cryoelectron Microscopy
  • Deubiquitinating Enzymes* / classification
  • Deubiquitinating Enzymes* / metabolism
  • Deubiquitinating Enzymes* / ultrastructure
  • Histones* / chemistry
  • Histones* / metabolism
  • Humans
  • Nucleosomes / chemistry
  • Nucleosomes / genetics
  • Nucleosomes / metabolism
  • Polycomb Repressive Complex 1* / chemistry
  • Polycomb Repressive Complex 1* / metabolism
  • Polycomb Repressive Complex 1* / ultrastructure
  • Polycomb-Group Proteins* / chemistry
  • Polycomb-Group Proteins* / metabolism
  • Polycomb-Group Proteins* / ultrastructure
  • Repressor Proteins / chemistry
  • Repressor Proteins / metabolism
  • Repressor Proteins / ultrastructure
  • Substrate Specificity
  • Ubiquitin / metabolism
  • Ubiquitin Thiolesterase / chemistry
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin Thiolesterase / ultrastructure
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / ultrastructure
  • Ubiquitination

Substances

  • Histones
  • Nucleosomes
  • Polycomb Repressive Complex 1
  • Polycomb-Group Proteins
  • Ubiquitin
  • Ubiquitin Thiolesterase
  • BAP1 protein, human
  • ASXL1 protein, human
  • Repressor Proteins
  • Deubiquitinating Enzymes
  • Ubiquitin-Protein Ligases