Histone Monoubiquitylation Position Determines Specificity and Direction of Enzymatic Cross-talk with Histone Methyltransferases Dot1L and PRC2

Whitcomb, Sarah J.; Fierz, Beat; McGinty, Robert K.; Holt, Matthew T.; Ito, Takashi; Muir, Tom W.; Allis, C. David

doi:10.1074/jbc.m112.361824

Cited by 35 publications

(31 citation statements)

References 45 publications

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“…The methylation of H3K79 by DOT1/DOT1L results from transhistone cross-talk that was initially found in combination with mono-ubiquitylation of H2B at K123 and K120 in yeast and mammals, respectively (Briggs et al, 2002;Krogan et al, 2003;Ng et al, 2003b;Ng et al, 2002;Sun and Allis, 2002;Wood et al, 2003). However, recent reports showed that several other types of H2B K ubiquitylation could lead to H3K79 methylation (Chatterjee et al, 2010;Whitcomb et al, 2012;Wu et al, 2011). Therefore, although exclusively catalyzed by DOT1/DOT1L, the methylation of H3K79 is a complex event in which several protein complexes are involved.…”

Section: Discussionmentioning

confidence: 99%

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

Sabra¹,

Texier²,

Maalouf³

et al. 2013

Journal of Cell Science

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SummarySpinal muscular atrophy (SMA) is a muscular disease characterized by the death of motoneurons, and is a major genetic cause of infant mortality. Mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), are responsible for the disease. SMN belongs to the Tudor domain protein family, whose members are known to interact with methylated arginine (R) or lysine (K) residues. SMN has well-defined roles in the metabolism of small non-coding ribonucleoproteins (snRNPs) and spliceosome activity. We previously showed that SMN relocated to damaged interphase centromeres, together with the Cajal-body-associated proteins coilin and fibrillarin, during the so-called interphase centromere damage response (iCDR). Here we reveal that SMN is a chromatin-binding protein that specifically interacts with methylated histone H3K79, a gene expression-and splicing-associated histone modification. SMN relocation to damaged centromeres requires its functional Tudor domain and activity of the H3K79 methyltransferase DOT1L. In vitro pulldown assays showed that SMN interacts with H3K79me1,2 at its functional Tudor domain. Chromatin immunoprecipitation confirmed that SMN binds to H3K79me1,2-containing chromatin in iCDR-induced cells. These data reveal a novel SMN property in the detection of specific chromatin modifications, and shed new light on the involvement of a putative epigenetic dimension to the occurrence of SMA.

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Section: Discussionmentioning

confidence: 99%

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

Sabra¹,

Texier²,

Maalouf³

et al. 2013

Journal of Cell Science

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“…Nonetheless, this histone nicely illustrates the sophistication of modern EPL strategies. Especially notable is the work of Fierz and colleagues (89, 117) on the preparation of H2A ubiquitylated at Lys-119 (H2AK119Ub). The semisynthesis was designed around three building blocks, two recombinant α-thioesters (produced by thiolysis of intein fusions) and a branched synthetic peptide.…”

Section: Semisynthesis Applied To Histonesmentioning

confidence: 99%

Application of the Protein Semisynthesis Strategy to the Generation of Modified Chromatin

Holt

Muir

2015

Annu. Rev. Biochem.

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Histone proteins are subject to a host of posttranslational modifications (PTMs) that modulate chromatin structure and function. Such control is achieved by the direct alteration of the intrinsic physical properties of the chromatin fiber or by regulating the recruitment and activity of a host of trans-acting nuclear factors. The sheer number of histone PTMs presents a formidable barrier to understanding the molecular mechanisms at the heart of epigenetic regulation of eukaryotic genomes. One aspect of this multifarious problem, namely how to access homogeneously modified chromatin for biochemical studies, is well suited to the sensibilities of the organic chemist. Indeed, recent years have witnessed a critical role for synthetic protein chemistry methods in generating the raw materials needed for studying how histone PTMs regulate chromatin biochemistry. This review focuses on what is arguably the most powerful, and widely employed, of these chemical strategies, namely histone semisynthesis via the chemical ligation of peptide fragments.

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“…Further, this linkage enables the dynamic removal of a protein modification via reduction of the disulfide bond, mimicking the dynamic behavior of protein modifications under controlled conditions. The Muir Laboratory exploited this approach to determine the position-dependent effect of ubiquitin in histones H2A and H2B while demonstrating that H2B ubiquitylation perturbs chromatin compaction[80, 81]. A similar approach was used to prepare histone H4 with sumoylation at H4-K12 in the N-terminal tail, and demonstrated that SUMO-3 inhibits higher order chromatin structure required for chromatin compaction [12].…”

Section: : Chemical Installation Of Ptm Analogs At Single Cysteine Smentioning

confidence: 99%

Chemical and Biological Tools for the Preparation of Modified Histone Proteins

Howard

Gardner

et al. 2015

Topics in Current Chemistry

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Eukaryotic chromatin is a complex and dynamic system in which the DNA double helix is organized and protected by interactions with histone proteins. This system is regulated through, a large network of dynamic post-translational modifications (PTMs) exists to ensure proper gene transcription, DNA repair, and other processes involving DNA. Homogenous protein samples with precisely characterized modification sites are necessary to better understand the functions of modified histone proteins. Here, we discuss sets of chemical and biological tools that have been developed for the preparation of modified histones, with a focus on the appropriate choice of tool for a given target. We start with genetic approaches for the creation of modified histones, including the incorporation of genetic mimics of histone modifications, chemical installation of modification analogs, and the use of the expanded genetic code to incorporate modified amino acids. Additionally, we will cover the chemical ligation techniques that have been invaluable in the generation of complex modified histones that are indistinguishable from the natural counterparts. Finally, we will end with a prospectus on future directions of synthetic chromatin in living systems.

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Histone Monoubiquitylation Position Determines Specificity and Direction of Enzymatic Cross-talk with Histone Methyltransferases Dot1L and PRC2

Cited by 35 publications

References 45 publications

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

Application of the Protein Semisynthesis Strategy to the Generation of Modified Chromatin

Chemical and Biological Tools for the Preparation of Modified Histone Proteins

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