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      The interplay of post-translational modification and gene therapy

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          Abstract

          Several proteins interact either to activate or repress the expression of other genes during transcription. Based on the impact of these activities, the proteins can be classified into readers, modifier writers, and modifier erasers depending on whether histone marks are read, added, or removed, respectively, from a specific amino acid. Transcription is controlled by dynamic epigenetic marks with serious health implications in certain complex diseases, whose understanding may be useful in gene therapy. This work highlights traditional and current advances in post-translational modifications with relevance to gene therapy delivery. We report that enhanced understanding of epigenetic machinery provides clues to functional implication of certain genes/gene products and may facilitate transition toward revision of our clinical treatment procedure with effective fortification of gene therapy delivery.

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          Most cited references 54

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          Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain.

          Heterochromatin protein 1 (HP1) is localized at heterochromatin sites where it mediates gene silencing. The chromo domain of HP1 is necessary for both targeting and transcriptional repression. In the fission yeast Schizosaccharomyces pombe, the correct localization of Swi6 (the HP1 equivalent) depends on Clr4, a homologue of the mammalian SUV39H1 histone methylase. Both Clr4 and SUV39H1 methylate specifically lysine 9 of histone H3 (ref. 6). Here we show that HP1 can bind with high affinity to histone H3 methylated at lysine 9 but not at lysine 4. The chromo domain of HP1 is identified as its methyl-lysine-binding domain. A point mutation in the chromo domain, which destroys the gene silencing activity of HP1 in Drosophila, abolishes methyl-lysine-binding activity. Genetic and biochemical analysis in S. pombe shows that the methylase activity of Clr4 is necessary for the correct localization of Swi6 at centromeric heterochromatin and for gene silencing. These results provide a stepwise model for the formation of a transcriptionally silent heterochromatin: SUV39H1 places a 'methyl marker' on histone H3, which is then recognized by HP1 through its chromo domain. This model may also explain the stable inheritance of the heterochromatic state.
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            The history of cancer epigenetics.

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              Protein modification by SUMO.

              Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level. Frequently SUMO alters interactions of substrates with other proteins or with DNA, but SUMO can also act by blocking ubiquitin attachment sites. An unusual feature of SUMO modification is that, for most substrates, only a small fraction of the substrate is sumoylated at any given time. This review discusses our current understanding of how SUMO conjugation is controlled, as well as the roles of SUMO in a number of biological processes.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                29 February 2016
                : 10
                : 861-871
                Affiliations
                [1 ]Covenant University Bioinformatics Research (CUBRe) Unit, Department of Computer and Information Sciences, College of Science and Technology (CST), Covenant University, Ota, Ogun State, Nigeria
                [2 ]Institute of Informatics (Computational biology and Bioinformatics), Faculty of Mathematics, Informatics and Mechanics, University of Warsaw (Uniwersytet Warszawski), Warszawa, Poland
                [3 ]Covenant University Public Health and Well-being Research Group (CUPHWERG), Covenant University, Canaan Land, Nigeria
                [4 ]Biochemistry and Molecular Biology Unit, Department of Biological Sciences, College of Science and Technology, Covenant University, Canaan Land, Nigeria
                [5 ]Department of Economics and Development Studies, Covenant University, Ota, Ogun State, Nigeria
                Author notes
                Correspondence: Victor Chukwudi Osamor, Department of Computer and Information Sciences, College of Science and Technology (CST), Covenant University, PMB 1023, Ota, Ogun State, Nigeria, Email vcosamor@ 123456gmail.com
                Article
                dddt-10-861
                10.2147/DDDT.S80496
                4778776
                27013864
                © 2016 Osamor et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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