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Class II histone deacetylases: versatile regulators 总被引:24,自引:0,他引:24
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HDAC's at work: everyone doing their part 总被引:5,自引:0,他引:5
Peterson CL 《Molecular cell》2002,9(5):921-922
The interplay between histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key to the dynamics of chromatin structure and function. A recent report of genome-wide, microarray maps of histone acetylation has uncovered the intragenic targets for six different yeast HDACs and has led to the discovery of new heterochromatin-like domains. 相似文献
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Durand-Dubief M Sinha I Fagerström-Billai F Bonilla C Wright A Grunstein M Ekwall K 《The EMBO journal》2007,26(10):2477-2488
Expression profiling, ChiP-CHIP and phenotypic analysis were used to investigate the functional relationships of class III NAD(+)-dependent HDACs (Sirtuins) in fission yeast. We detected significant histone acetylation increases in Sirtuin mutants at their specific genomic binding targets and were thus able to identify an in vivo substrate preference for each Sirtuin. At heterochromatic loci, we demonstrate that although Hst2 is mainly cytoplasmic, a nuclear pool of Hst2 colocalizes with the other Sirtuins at silent regions (cen, mat, tel, rDNA), and that like the other Sirtuins, Hst2 is required for rDNA and centromeric silencing. Interestingly we found specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation. Hst2 directly represses genes involved in transport and membrane function, whereas Hst4 represses amino-acid biosynthesis genes and Tf2 retrotransposons. A specific role for Hst4 in Tf2 5' mRNA processing was revealed. Thus, Sirtuins share functions at many genomic targets, but Hst2 and Hst4 have also evolved unique functions in gene regulation. 相似文献
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Mutational switching of a yeast tRNA synthetase into a mammalian-like synthetase cytokine 总被引:1,自引:0,他引:1
Aminoacyl-tRNA synthetases catalyze the attachment of amino acids to their cognate tRNAs. A link was recently established between protein biosynthesis and cytokine signal transduction. Human tyrosyl-tRNA synthetase can be split into two fragments, each of which has a distinct cytokine function. This activity is specific to the human enzyme. It is absent in the enzymes from lower organisms such as bacteria and yeast. Here, yeast tyrosyl-tRNA synthetase (TyrRS), which lacks cytokine activity, was used as a model to explore how a human tyrosyl-tRNA synthetase during evolution acquired novel functions beyond aminoacylation. We found that a rationally designed mutant yeast TyrRS(ELR) gained cytokine function. The mutant yeast enzyme gained this function without sacrifice of aminoacylation activity. Therefore, relatively simple alteration of a basic structural motif imparts cytokine activity to a tRNA synthetase while preserving its canonical function. Further work established that mutational switching of a yeast protein to a mammalian-like cytokine was specific to this synthetase and not to just any yeast ortholog of a mammalian cytokine. 相似文献
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The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC 11. Class III HDACs, sirtuins 1–7, have an absolute requirement for NAD+, are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti‐cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T‐cell lymphoma. J. Cell. Biochem. 107: 600–608, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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Dard N Peter M 《BioEssays : news and reviews in molecular, cellular and developmental biology》2006,28(2):146-156
Due to the central position of scaffold proteins in numerous signaling networks, especially in MAPK pathways, considerable efforts have been made to identify new scaffolds and to characterize their function and regulation. Most of our knowledge stems from studies of yeast MAPK scaffolds, but the identification of such scaffolds in higher eukaryotes provided a new dimension to this field and led to exciting and promising new insights into the regulation of MAPK signaling. In this review, we shortly summarize the well-established basic functions of scaffolds in yeast and highlight concepts emerging from recent studies in yeast and higher eukaryotes. In particular, we discuss how scaffolds may actively influence MAPK signaling by inducing conformational changes of bound kinases or substrates, by controlling the localization of activated MAPK and the extent and output of MAPK activation, and by modulating MAPK kinetics through the recruitment of phosphatases or ubiquitin-ligases. Finally, we summarize the current knowledge of scaffold regulation, and how these events may be functionally important for MAPK signaling. 相似文献
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《TARGETS》2003,2(3):85-92
The availability of complete genome sequences of numerous model organisms has initiated the development of new approaches in biological research to complement conventional biochemistry and genetics. In this context, high-throughput methods for detecting protein interactions, such as mass spectrometry and yeast two-hybrid assays, have produced vast amounts of data that can be exploited to infer protein function and regulation. In this review, we explore different genome-wide protein interaction studies and comment on their extrapolation towards understanding protein functions. It is likely that improvements of these approaches, together with more sophisticated databases and the invention of novel technologies, will help to decipher the complex interactions among proteins and to integrate interacting proteins into existing and novel cellular pathways. 相似文献
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Lu TK 《Bioengineered bugs》2010,1(6):378-384
Synthetic biology is focused on engineering biological organisms to study natural systems and to provide new solutions for pressing medical, industrial and environmental problems. At the core of engineered organisms are synthetic biological circuits that execute the tasks of sensing inputs, processing logic and performing output functions. In the last decade, significant progress has been made in developing basic designs for a wide range of biological circuits in bacteria, yeast and mammalian systems. However, significant challenges in the construction, probing, modulation and debugging of synthetic biological systems must be addressed in order to achieve scalable higher-complexity biological circuits. Furthermore, concomitant efforts to evaluate the safety and biocontainment of engineered organisms and address public and regulatory concerns will be necessary to ensure that technological advances are translated into real-world solutions. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(3):406-412
Histone deacetylases (HDACs) are negative regulators of gene expression and have been implicated in tumorigenesis and tumor progression. Therefore, HDACs are promising targets for anti-tumor drugs. However, the relevant isoforms of the 18 members encompassing HDAC family have not been identified. Studies utilizing either gene targeting or knockdown approaches reveal both specific and redundant functions of the closely related class I deacetylases HDAC1 and HDAC2 in the control of proliferation and differentiation. Combined ablation of HDAC1 and HDAC2 in different cell types led to a severe proliferation defects or enhanced apoptosis supporting the idea that both enzymes are relevant targets for tumor therapy. In a recent study on the role of HDAC1 in teratoma formation we have reported a novel and surprising function of HDAC1 in tumorigenesis. In this tumor model HDAC1 attenuates proliferation during teratoma formation. In the present work we discuss new findings on redundant and unique functions of HDAC1 and HDAC2 as regulators of proliferation and tumorigenesis and potential implications for applications of HDAC inhibitors as therapeutic drugs. 相似文献
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Gene duplication as a major force in evolution 总被引:4,自引:0,他引:4
SANTOSHKUMAR MAGADUM URBI BANERJEE PRIYADHARSHINI MURUGAN DODDABHIMAPPA GANGAPUR RAJASEKAR RAVIKESAVAN 《Journal of genetics》2013,92(1):155-161
Gene duplication is an important mechanism for acquiring new genes and creating genetic novelty in organisms. Many new gene functions have evolved through gene duplication and it has contributed tremendously to the evolution of developmental programmes in various organisms. Gene duplication can result from unequal crossing over, retroposition or chromosomal (or genome) duplication. Understanding the mechanisms that generate duplicate gene copies and the subsequent dynamics among gene duplicates is vital because these investigations shed light on localized and genomewide aspects of evolutionary forces shaping intra-specific and inter-specific genome contents, evolutionary relationships, and interactions. Based on whole-genome analysis of Arabidopsis thaliana, there is compelling evidence that angiosperms underwent two whole-genome duplication events early during their evolutionary history. Recent studies have shown that these events were crucial for creation of many important developmental and regulatory genes found in extant angiosperm genomes. Recent studies also provide strong indications that even yeast (Saccharomyces cerevisiae), with its compact genome, is in fact an ancient tetraploid. Gene duplication can provide new genetic material for mutation, drift and selection to act upon, the result of which is specialized or new gene functions. Without gene duplication the plasticity of a genome or species in adapting to changing environments would be severely limited. Whether a duplicate is retained depends upon its function, its mode of duplication, (i.e. whether it was duplicated during a whole-genome duplication event), the species in which it occurs, and its expression rate. The exaptation of preexisting secondary functions is an important feature in gene evolution, just as it is in morphological evolution. 相似文献