Tang, Y. et al. Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. Nature Struct. Mol. Biol. 15, 738-745

Program in Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Nature Structural & Molecular Biology (Impact Factor: 13.31). 08/2008; 15(7):738-45. DOI: 10.1038/nsmb.1448
Source: PubMed


Rtt109, also known as KAT11, is a recently characterized fungal-specific histone acetyltransferase (HAT) that modifies histone H3 lysine 56 (H3K56) to promote genome stability. Rtt109 does not show sequence conservation with other known HATs and depends on association with either of two histone chaperones, Asf1 or Vps75, for HAT activity. Here we report the X-ray crystal structure of an Rtt109-acetyl coenzyme A complex and carry out structure-based mutagenesis, combined with in vitro biochemical studies of the Rtt109-Vps75 complex and studies of Rtt109 function in vivo. The Rtt109 structure reveals noteworthy homology to the metazoan p300/CBP HAT domain but exhibits functional divergence, including atypical catalytic properties and mode of cofactor regulation. The structure reveals a buried autoacetylated lysine residue that we show is also acetylated in the Rtt109 protein purified from yeast cells. Implications for understanding histone substrate and chaperone binding by Rtt109 are discussed.

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    • "The p300/ CBP family is restricted to animals. Instead in fungi, there exists a fungal specific structural homolog, Rtt109 (Tang et al., 2008). It is responsible for the acetylation of H3K56 (Schneider et al., 2006), a histone residue at the DNA entry and exit point in the core of a nucleosome (Wang et al., 2008) as opposed to the more accessible N-terminal histone tail residues usually targeted by HATs for transcriptional regulation. "
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    ABSTRACT: Acetylation of histone lysine residues occurs in different organisms ranging from yeast to plants and mammals for the regulation of diverse cellular processes. With the identification of enzymes that create or reverse this modification, our understanding on histone acetylation has expanded at an amazing pace during the last two decades. In fungal pathogens of plants, however, the importance of such modification has only just begun to be appreciated in the recent years and there is a dearth of information on how histone acetylation is implicated in fungal pathogenesis. This review covers the current status of research related to histone acetylation in plant pathogenic fungi and considers relevant findings in the interaction between fungal pathogens and host plants. We first describe the families of histone acetyltransferases and deacetylases. Then we provide the cases where histone acetylation was investigated in the context of fungal pathogenesis. Finally, future directions and perspectives in epigenetics of fungal pathogenesis are discussed.
    The plant pathology journal 03/2014; 30(1). DOI:10.5423/PPJ.RW.01.2014.0003 · 0.72 Impact Factor
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    • "Acetylation of histone H3 K56 is catalyzed by p300/CBP in higher eukaryotes [84] and by Rtt109 (the structural homolog of p300/CBP [85]) in yeast [43–46]. This histone modification has been shown to be stimulated by the histone chaperone ASF1 in all organisms studied. "
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    ABSTRACT: Histones are highly alkaline proteins that package and order the DNA into chromatin in eukaryotic cells. Nucleotide excision repair (NER) is a conserved multistep reaction that removes a wide range of generally bulky and/or helix-distorting DNA lesions. Although the core biochemical mechanism of NER is relatively well known, how cells detect and repair lesions in diverse chromatin environments is still under intensive research. As with all DNA-related processes, the NER machinery must deal with the presence of organized chromatin and the physical obstacles it presents. A huge catalogue of posttranslational histone modifications has been documented. Although a comprehensive understanding of most of these modifications is still lacking, they are believed to be important regulatory elements for many biological processes, including DNA replication and repair, transcription and cell cycle control. Some of these modifications, including acetylation, methylation, phosphorylation and ubiquitination on the four core histones (H2A, H2B, H3 and H4) or the histone H2A variant H2AX, have been found to be implicated in different stages of the NER process. This review will summarize our recent understanding in this area.
    International Journal of Molecular Sciences 12/2012; 13(10):12461-86. DOI:10.3390/ijms131012461 · 2.86 Impact Factor
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    • "3Q66 AcCoA Full length 3Q68 AcCoA Full length [342] Type B Rtt109 Saccharomyces cerevisiae 3QM0 AcCoA HAT [343] "
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    ABSTRACT: Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of small-molecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.
    Current pharmaceutical design 09/2012; 19(4). DOI:10.2174/138161213804581918 · 3.45 Impact Factor
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