Histone H2B ubiquitination and beyond

Department of Biochemistry and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
Epigenetics: official journal of the DNA Methylation Society (Impact Factor: 4.78). 08/2010; 5(6):460-8. DOI: 10.4161/epi.5.6.12314
Source: PubMed

ABSTRACT Regulation of Set1-COMPASS-mediated H3K4 methylation and Dot1-mediated H3K79 methylation by H2BK123 ubiquitination (H2Bub1) is an evolutionarily conserved trans-histone crosstalk mechanism. How H2Bub1 impacts chromatin structure and affects Set1-COMPASS/Dot1 functions has not been fully defined. Ubiquitin was proposed to bind proteins to physically bridge H2Bub1 with Set1-COMPASS/Dot1. Alternatively, the bulky ubiquitin was thought to be a "wedge" that loosens the nucleosome for factor access. Contrary to the latter possibility, recent discoveries provide evidence for nucleosome stabilization by H2Bub1 via preventing the constant H2A-H2B eviction. Recent data has also uncovered a "docking-site" on H2B for Set1-COMPASS. Collectively, these findings invoke a model, where ubiquitin acts as a "glue" to bind the nucleosome together for supporting Set1-COMPASS/Dot1 functions. This review provides an overview of these novel findings. Additionally, how H2Bub1 and its deubiquitination might alter the chromatin dynamics during transcription is discussed. Possible models for nucleosome stabilization by ubiquitin are also provided.

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Available from: Mahesh B Chandrasekharan, Sep 27, 2015
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    • "In particular, all the ESCRT-I subunits are involved in transcriptional regulation (Figs 1, 2, 4) and some of these components (Vps23 and Mvb12) contain the domain for binding to ubiquitylated proteins. Thus, we examined whether the ESCRT-I complex interacts with or modulates the ubiquitylation of histone H2B, a modification closely associated with the activation of transcription through the methylation of histone H3 at lysine residues 4 and 79 (Chandrasekharan et al. 2010; Song and Ahn 2010; Sun and Allis 2002). To examine histone ubiquitylation, we used a yeast strain containing the Flag-tagged HTB1 gene and the hemagglutinin (HA)-tagged UBI4 gene as WT. "
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    ABSTRACT: Endosomal sorting complex required for transport (ESCRT) is involved in membrane protein degradation through the recognition and sorting of ubiquitylated cargo proteins into the multivesicular body before fusion with the lysosome/vacuole. However, recent studies have challenged this canonical cellular function of ESCRT and have implicated a role for this machinery in multiple intracellular pathways. Here, we provide evidence that ESCRT complexes contribute to the regulation of transcription elongation in Saccharomyces cerevisiae. Most strains deficient in each subunit of ESCRT-0, -I, -II, and -III showed significant sensitivity to 6-azauracil or mycophenolic acid, a phenotype associated with transcription elongation defects. Moreover, these deletion strains significantly reduced transcription activation through Gcn4, a regulator of the general amino acid control. The transcription factor Rim101, which is proteolytically activated through the multimerized component Vps32/Snf7 of ESCRT-III and its collaborative proteins, was not associated with transcription elongation or Gcn4 activation. In addition, we observed that ESCRT complexes were crosslinked at the 3′ region of the coding sequence in the actively transcribed gene. In summary, these results suggest that ESCRT complexes promote genes transcription during the late stages of elongation and are required for transcription activation through Gcn4.
    Genes & genomics 06/2014; 36(3). DOI:10.1007/s13258-013-0171-8 · 0.60 Impact Factor
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    • "The experiments described herein do not allow discrimination between a direct or indirect influence of H4 hyperacetylation on the methylation of histone H3K79. A so-called trans-histone crosstalk, in which efficient methylation of lysine H3K79 directly depends on ubiquitinated histone H2B is known to regulate chromatin dynamics during transcription and telomeric silencing in yeast and Drosophila (for reviews, see Chandrasekharan et al., 2010; Wood et al., 2005; Mohan et al., 2010). We observed that H3K79 methylation in Drosophila is largely blocked if H4 hyperacetylation is inhibited, in agreement with the strongly reduced level of Gpp. "
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    ABSTRACT: During spermiogenesis, haploid spermatids undergo extensive chromatin remodeling events in which histones are successively replaced by more basic protamines to generate highly compacted chromatin. Here we show for the first time that H3K79 methylation is a conserved feature preceding the histone-to-protamine transition in Drosophila melanogaster and rat. During Drosophila spermatogenesis, the Dot1-like methyltransferase Grappa (Gpp) is primarily expressed in canoe stage nuclei. The corresponding H3K79 methylation is a histone modification that precedes the histone-to-protamine transition and correlates with histone H4 hyperacetylation. When acetylation was inhibited in cultured Drosophila testes, nuclei were smaller and chromatin was compact, Gpp was little synthesized, H3K79 methylation was strongly reduced, and protamines were not synthesized. The Gpp isoform Gpp-D has a unique C-terminus, and Gpp is essential for full fertility. In rat, H3K79 methylation also correlates with H4 hyperacetylation but not with active RNA polymerase II, which might point towards a conserved function in chromatin remodeling during the histone-to-protamine transition in both Drosophila and rat.
    Biology Open 05/2014; 3(6). DOI:10.1242/bio.20147302 · 2.42 Impact Factor
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    • "However, the precise functions of Lys 112 ubiquitination have yet to be fully defined. A previous report had shown ubiquitination of histone H2BK123 enhanced its binding activity and stabilized nucleosome (Chandrasekharan et al., 2010). It is implicated that methylation of HMGB1 at Lys112 reduces its DNA-binding ability through the substitution of Lys112 ubiquitination. "
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    ABSTRACT: Background: The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.
    Asian Pacific journal of cancer prevention: APJCP 10/2013; 14(10):5789-95. DOI:10.7314/APJCP.2013.14.10.5789 · 2.51 Impact Factor
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