A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation

Mol Cell. 2007 Aug 17;27(4):609-21. doi: 10.1016/j.molcel.2007.07.024.


Deciphering the epigenetic "code" remains a central issue in transcriptional regulation. Here, we report the identification of a JAMM/MPN(+) domain-containing histone H2A deubiquitinase (2A-DUB, or KIAA1915/MYSM1) specific for monoubiquitinated H2A (uH2A) that has permitted delineation of a strategy for specific regulatory pathways of gene activation. 2A-DUB regulates transcription by coordinating histone acetylation and deubiquitination, and destabilizing the association of linker histone H1 with nucleosomes. 2A-DUB interacts with p/CAF in a coregulatory protein complex, with its deubiquitinase activity modulated by the status of acetylation of nucleosomal histones. Consistent with this mechanistic role, 2A-DUB participates in transcriptional regulation events in androgen receptor-dependent gene activation, and the levels of uH2A are dramatically decreased in prostate tumors, serving as a cancer-related mark. We suggest that H2A ubiquitination represents a widely used mechanism for many regulatory transcriptional programs and predict that various H2A ubiquitin ligases/deubiquitinases will be identified for specific cohorts of regulated transcription units.

Publication types

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

MeSH terms

  • Acetylation / drug effects
  • Androgens / pharmacology
  • Animals
  • Cell Line
  • Chromatography, Affinity
  • DNA-Binding Proteins / isolation & purification
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation* / drug effects
  • Histone Acetyltransferases / metabolism
  • Histones / metabolism*
  • Humans
  • Mice
  • Models, Genetic
  • Nucleosomes / drug effects
  • Nucleosomes / metabolism
  • Phosphorylation / drug effects
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • Trans-Activators
  • Transcription Factors / isolation & purification
  • Transcription Factors / metabolism*
  • Transcription, Genetic* / drug effects
  • Transcriptional Activation / drug effects
  • Ubiquitin-Specific Proteases
  • Ubiquitins / metabolism*


  • AR protein, human
  • Androgens
  • DNA-Binding Proteins
  • Histones
  • MYSM1 protein, human
  • Nucleosomes
  • Receptors, Androgen
  • Trans-Activators
  • Transcription Factors
  • Ubiquitins
  • chromatin conjugate protein A24
  • Histone Acetyltransferases
  • Ubiquitin-Specific Proteases