Binding of Antitumor Antibiotic Daunomycin to Histones in Chromatin and in Solution †

Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Biochemistry (Impact Factor: 3.02). 01/2005; 43(51):16497-504. DOI: 10.1021/bi048524p
Source: PubMed


Daunomycin is an anticancer drug that is well-known to interact with DNA in chromatin. Using a compositionally defined chicken erythrocyte chromatin fraction, we have obtained conclusive evidence that the drug is also able to interact with chromatin-bound linker histones without any noticeable binding to core histones. The drug can interact in an equal fashion with both histone H1 and H5 and to a greater extent with core histones H3/H4 and H2A/H2B as free proteins in solution. Thus, the binding of daunomycin to linker histones in the chromatin fiber is most likely due to the well-known higher accessibility of these histones to the surrounding environment of the fiber. Binding of daunomycin to linker histones appears to primarily involve the trypsin-resistant (winged-helix) domain of these proteins. The studies described here reveal the occurrence of a previously undisclosed mechanism for the antitumor activity of anthracycline drugs at the chromatin level.

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    • "The former class of ligands binds to chromosomal DNA only while the later has the ability to bind both histone(s) and chromosomal DNA. Studies from our laboratory and others had shown that the plant alkaloid sanguinarine [7], daunomycin and mitoxantrone [8] [9] interact with both DNA and core histones and affect post-translational modifications like histone acetylation [10]. With the above broad objective, we have investigated the chromatin binding properties of a classical DNA intercalator, ethidium bromide and its structural longer analogue, propidium iodide 2211-5463/Ó 2014 The Authors. "
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    ABSTRACT: Eukaryotic DNA is compacted in the form of chromatin, in a complex with histones and other nonhistone proteins. The intimate association of DNA and histones in chromatin raises the possibility that DNA-interactive small molecules may bind to chromatin-associated proteins such as histones. Employing biophysical and biochemical techniques we have characterized the interaction of a classical intercalator, ethidium bromide (EB) and its structural analogue propidium iodide (PI) with hierarchical genomic components: long chromatin, chromatosome, core octamer and chromosomal DNA. Our studies show that EB and PI affect both chromatin structure and function, inducing chromatin compaction and disruption of the integrity of the chromatosome. Calorimetric studies and fluorescence measurements of the ligands demonstrated and characterized the association of these ligands with core histones and the intact octamer in absence of DNA. The ligands affect acetylation of histone H3 at lysine 9 and acetylation of histone H4 at lysine 5 and lysine 8 ex vivo. PI alters the post-translational modifications to a greater extent than EB. This is the first report showing the dual binding (chromosomal DNA and core histones) property of a classical intercalator, EB, and its longer analogue, PI, in the context of chromatin. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. This is an open access article under the CC BY license.
    FEBS Open Bio 02/2014; 4. DOI:10.1016/j.fob.2014.02.006 · 1.52 Impact Factor
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    • "By binding to guanine-cytosine-rich regions within gene promoters, anthracyclines displace transcriptional elements that activate and repress transcription (Chakrabarti et al., 2000). Importantly, anthracyclines have been reported to interact directly with histones H3 and H4 (Rabbani et al., 2004). This has lead to several preclinical studies investigating the potential utility of mithramycin or chromomycin in murine models of HD (Ferrante et al., 2004; Ryu et al., 2006; Stack et al., 2007b). "
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    ABSTRACT: Huntington's disease (HD) is an autosomal dominant, progressive, and fatal neurodegenerative disorder caused by an expanded polyglutamine cytosine-adenine-guanine repeat in the gene coding for the protein huntingtin. Despite great progress over the past two decades since the identification of the gene mutation, a direct causative pathway from the HD gene mutation to neuronal dysfunction and death has not yet been established. One important advance in understanding the pathogenic mechanisms of this disease has been the development of experimental mouse models that replicate many of the clinical, neuropathological, and molecular events in HD patients. These murine models have played a critical role in providing accurate and experimentally accessible systems to study multiple features of disease pathogenesis and to test potential therapeutic strategies. A better understanding of the pathophysiological mechanisms of disease and how they interrelate has become important in identifying a treatment for HD and in the design of human clinical trials. In this chapter, we review the current state of HD mouse models and their successes in elucidating disease pathogenesis and in developing pharmacotherapies. There is no clinically proven treatment for HD that can halt or ameliorate the inexorable disease progression. As such, a guide to assessing studies in mouse models and salient issues related to translation from mice to humans are included.
    International Review of Neurobiology 01/2011; 98:419-81. DOI:10.1016/B978-0-12-381328-2.00016-X · 1.92 Impact Factor
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    • "The antitumor affects of anthracyclines are attributed to the ability of the molecules to inhibit topoisomerase by intercalating DNA, and the specifics of this interaction are very well-characterized (24–32). However, the ability of these drugs to intercalate double-stranded RNA has largely been neglected in the literature. "
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    ABSTRACT: Double-stranded sections of mRNA are often inviting sites of interaction for a wide variety of proteins and small molecules. Interactions at these sites can serve to regulate, or disrupt, the homeostasis of the encoded protein products. Such ligand target sites exist as hairpin-loop structures in the mRNAs of several of the proteins involved in iron homeostasis, including ferritin heavy and light chains, and are known as iron responsive elements (IREs). These IREs serve as the main control mechanism for iron metabolism in the cell via their interaction with the iron regulatory proteins (IRPs). Disruption of the IRE/IRP interaction could greatly affect iron metabolism. Here, we report that anthracyclines, a class of clinically useful chemotherapeutic drugs that includes doxorubicin and daunorubicin, specifically interact with the IREs of ferritin heavy and light chains. We characterized this interaction through UV melting, fluorescence quenching and drug-RNA footprinting. Results from footprinting experiments with wild-type and mutant IREs indicate that anthracyclines preferentially bind within the UG wobble pairs flanking an asymmetrically bulged C-residue, a conserved base that is essential for IRE-IRP interaction. Additionally, drug-RNA affinities (apparent K(d)s) in the high nanomolar range were calculated from fluorescence quenching experiments, while UV melting studies revealed shifts in melting temperature (DeltaT(m)) as large as 10 degrees C. This anthracycline-IRE interaction may contribute to the aberration of intracellular iron homeostasis that results from anthracycline exposure.
    Nucleic Acids Research 11/2008; 36(21):6825-34. DOI:10.1093/nar/gkn774 · 9.11 Impact Factor
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