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: 14.02). 09/2007; 27(4):609-21. DOI: 10.1016/j.molcel.2007.07.024
Source: PubMed


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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Available from: Hediye Erdjument-Bromage, May 22, 2014
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    • "Deubiquitinases (DUBs) are proteases that specifically cleave ubiquitin linkages thereby reversing the action of ubiquitin ligases (Komander et al., 2009). The H2A deubiquitinase myb-like SWIRM and MPN domains 1 (MYSM1, also known as 2A-DUB or KIAA1915) is a metalloprotease previously reported to target monoubiquitinated histone H2A, a mark for epigenetic transcriptional repression and chromatin inaccessibility (Jiang et al., 2011; Nandakumar et al., 2013; Nijnik et al., 2012; Wang et al., 2013; Zhu et al., 2007). Here we show that beyond its role in the nucleus, MYSM1 was a key negative regulator of innate immunity that rapidly accumulated in the cytoplasm to inhibit proximal PRR signaling upon microbial stimuli. "
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    ABSTRACT: Pattern-recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, and cytoplasmic DNA receptors are essential for protection against pathogens but require tight control to avert inflammatory diseases. The mechanisms underlying this strict regulation are unclear. MYSM1 was previously described as a key component of epigenetic signaling machinery. We found that in response to microbial stimuli, MYSM1 accumulated in the cytoplasm where it interacted with and inactivated TRAF3 and TRAF6 complexes to terminate PRR pathways for pro-inflammatory and type I interferon responses. Consequently, Mysm1 deficiency in mice resulted in hyper-inflammation and enhanced viral clearance but also susceptibility to septic shock. We identified two motifs in MYSM1 that were essential for innate immune suppression: the SWIRM domain that interacted with TRAF3 and TRAF6 and the metalloproteinase domain that removed K63 polyubiquitins. This study identifies MYSM1 as a key negative regulator of the innate immune system that guards against an overzealous self-destructive immune response.
    Immunity 10/2015; DOI:10.1016/j.immuni.2015.09.010 · 21.56 Impact Factor
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    • " , Coleman and Greenberg ( 2011 ) , Hu et al . ( 2011 ) , Zheng et al . ( 2013 ) MYSM1 / 2A - DUB H2A Promotes DSB repair . Sensitization : IR 1 Transcription Mysm1 - null mice display partial embryonic lethality , growth retardation , epidermal abnormalities , multi - lineage hematopoietic defects , HSC deficiencies and predisposition to lymphoma Zhu et al . ( 2007 ) , Jiang et al . ( 2011 ) , Nijnik et al . ( 2012 ) , Nandakumar et al . ( 2013 ) , Wang et al . ( 2013 ) , DiTommaso et al . ( 2014 ) , Liakath - Ali et al . ( 2014 ) , Nishi et al . ( 2014 ) , Won et al . ( 2014 ) , Belle et al . ( 2015 ) , Gatzka et al . ( 2015 ) POH1 / PSMD14 K63 - ub Restricts 53BP1 ; promotes RAD51 ; sensitizatio"
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    ABSTRACT: Ubiquitination is a reversible protein modification broadly implicated in cellular functions. Signaling processes mediated by ubiquitin are crucial for the cellular response to DNA double-strand breaks (DSBs), one of the most dangerous types of DNA lesions. In particular, the DSB response critically relies on active ubiquitination by the RNF8 and RNF168 ubiquitin ligases at the chromatin, which is essential for proper DSB signaling and repair. How this pathway is fine-tuned and what the functional consequences are of its deregulation for genome integrity and tissue homeostasis are subject of intense investigation. One important regulatory mechanism is by reversal of substrate ubiquitination through the activity of specific deubiquitinating enzymes (DUBs), as supported by the implication of a growing number of DUBs in DNA damage response (DDR) processes. Here, we discuss the current knowledge of how ubiquitin-mediated signaling at DSBs is controlled by deubiquitinating enzymes, with main focus on DUBs targeting histone H2A and on their recent implication in stem cell biology and cancer.
    Frontiers in Genetics 09/2015; 08(September 2015):Article 282. DOI:10.3389/fgene.2015.00282
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    • "DUBs regulate their substrates not only by determining their proteolytic fate. For example, as it was also shown in plants, histone H2A or histone H2B ubiquitylation status is controlled by multiple DUBs (Joo et al., 2007; Sridhar et al., 2007; Zhu et al., 2007; Nakagawa et al., 2008; Schmitz et al., 2009). The ubiquitylation status of histones affects their methylation status and thus controls gene expression in the corresponding chromatin region. "
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    ABSTRACT: Ubiquitylation is a reversible post-translational modification that is involved in various cellular pathways and that thereby regulates various aspects of plant biology. For a long time, functional studies of ubiquitylation have focused on the function of ubiquitylating enzymes, especially the E3 ligases, rather than deubiquitylating enzymes (DUBs) or ubiquitin isopeptidases, enzymes that hydrolyze ubiquitin chains. One reason may be the smaller number of DUBs in comparison to E3 ligases, implying the broader substrate specificities of DUBs and the difficulties to identify the direct targets. However, recent studies have revealed that DUBs also actively participate in controlling cellular events and thus play pivotal roles in plant development and growth. DUBs are also essential for processing ubiquitin precursors and are important for recycling ubiquitin molecules from target proteins prior to their degradation and thereby maintaining the free ubiquitin pool in the cell. Here, we will discuss the five different DUB families (USP/UBP, UCH, JAMM, OTU, and MJD) and their known biochemical and physiological roles in plants.
    Frontiers in Plant Science 02/2014; 5:56. DOI:10.3389/fpls.2014.00056 · 3.95 Impact Factor
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