A histone H2A deubiquitinase complex coordinating histone acetylation and H1 dissociation in transcriptional regulation.
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.
Zhu
Ping
P
Howard Hughes Medical Institute, Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Zhou
Wenlai
W
Wang
Jianxun
J
Puc
Janusz
J
Ohgi
Kenneth A
KA
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D000107:Acetylation / Q000187:drug effects; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002846:Chromatography, Affinity; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014157:Transcription Factors / Q000302:isolation & purification / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D064570:Ubiquitin-Specific Proteases; D014452:Ubiquitins / Q000378:metabolism*
C410798:AR protein, human; D000728:Androgens; D004268:DNA-Binding Proteins; D006657:Histones; C520745:MYSM1 protein, human; D009707:Nucleosomes; D011944:Receptors, Androgen; D015534:Trans-Activators; D014157:Transcription Factors; D014452:Ubiquitins; C021645:chromatin conjugate protein A24; D051548:Histone Acetyltransferases; D064570:Ubiquitin-Specific Proteases
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