A Histone H2A Deubiquitinase Complex Coordinating Histone Acetylation and H1 Dissociation in Transcriptional Regulation

Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Molecular Cell (Impact Factor: 14.46). 09/2007; 27(4):609-21. DOI: 10.1016/j.molcel.2007.07.024
Source: PubMed

ABSTRACT 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.

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