BAP1 enhances Polycomb repression by counteracting widespread H2AK119ub1 deposition and chromatin condensation

Mol Cell. 2021 Sep 2;81(17):3526-3541.e8. doi: 10.1016/j.molcel.2021.06.020. Epub 2021 Jun 28.


BAP1 is mutated or deleted in many cancer types, including mesothelioma, uveal melanoma, and cholangiocarcinoma. It is the catalytic subunit of the PR-DUB complex, which removes PRC1-mediated H2AK119ub1, essential for maintaining transcriptional repression. However, the precise relationship between BAP1 and Polycombs remains elusive. Using embryonic stem cells, we show that BAP1 restricts H2AK119ub1 deposition to Polycomb target sites. This increases the stability of Polycomb with their targets and prevents diffuse accumulation of H2AK119ub1 and H3K27me3. Loss of BAP1 results in a broad increase in H2AK119ub1 levels that is primarily dependent on PCGF3/5-PRC1 complexes. This titrates PRC2 away from its targets and stimulates H3K27me3 accumulation across the genome, leading to a general chromatin compaction. This provides evidence for a unifying model that resolves the apparent contradiction between BAP1 catalytic activity and its role in vivo, uncovering molecular vulnerabilities that could be useful for BAP1-related pathologies.

Keywords: BAP1; H2AK119ub1; PCGF3; PR-DUB; PRC1; PRC2; Polycomb; chromatin compaction; transcriptional repression; tumor suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin / physiology
  • Embryonic Stem Cells / metabolism
  • Heterochromatin
  • Histones / metabolism
  • Humans
  • Mice
  • Mouse Embryonic Stem Cells / metabolism
  • Polycomb Repressive Complex 1 / metabolism
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb-Group Proteins / genetics
  • Polycomb-Group Proteins / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / physiology
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin Thiolesterase / physiology
  • Ubiquitination


  • BAP1 protein, mouse
  • Chromatin
  • Heterochromatin
  • Histones
  • Polycomb-Group Proteins
  • Tumor Suppressor Proteins
  • Polycomb Repressive Complex 2
  • Polycomb Repressive Complex 1
  • Ubiquitin Thiolesterase