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      Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin

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          Abstract

          DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage response, is also evicted by anthracyclines, and H2AX eviction is associated with attenuated DNA repair. Histone eviction deregulates the transcriptome in cancer cells and organs such as the heart, and can drive apoptosis of topoisomerase-negative acute myeloid leukaemia blasts in patients. We define a novel mechanism of action of anthracycline anticancer drugs doxorubicin and daunorubicin on chromatin biology, with important consequences for DNA damage responses, epigenetics, transcription, side effects and cancer therapy.

          Abstract

          Anthracycline-based drugs can kill cancer cells by inhibiting topoisomerase II and promoting DNA double-strand breaks. Pang et al. show that anthracyclines also induce eviction of histones from open chromatin regions and, in doing so, modulate DNA repair and apoptosis in human cancer cells.

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          Most cited references 36

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          MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.

          Histone variant H2AX phosphorylation in response to DNA damage is the major signal for recruitment of DNA-damage-response proteins to regions of damaged chromatin. Loss of H2AX causes radiosensitivity, genome instability, and DNA double-strand-break repair defects, yet the mechanisms underlying these phenotypes remain obscure. Here, we demonstrate that mammalian MDC1/NFBD1 directly binds to phospho-H2AX (gammaH2AX) by specifically interacting with the phosphoepitope at the gammaH2AX carboxyl terminus. Moreover, through a combination of biochemical, cell-biological, and X-ray crystallographic approaches, we reveal the molecular details of the MDC1/NFBD1-gammaH2AX complex. These data provide compelling evidence that the MDC1/NFBD1 BRCT repeat domain is the major mediator of gammaH2AX recognition following DNA damage. We further show that MDC1/NFBD1-gammaH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin. Thus, binding of MDC1/NFBD1 to gammaH2AX plays a central role in the mammalian response to DNA damage.
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            Genomic instability in mice lacking histone H2AX.

            Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.
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              CEAS: cis-regulatory element annotation system.

              We present a tool designed to characterize genome-wide protein-DNA interaction patterns from ChIP-chip and ChIP-Seq data. This stand-alone extension of our web application CEAS (cis-regulatory element annotation system) provides summary statistics on ChIP enrichment in important genomic regions such as individual chromosomes, promoters, gene bodies or exons, and infers the genes most likely to be regulated by the binding factor under study. CEAS also enables biologists to visualize the average ChIP enrichment signals over specific genomic regions, particularly allowing observation of continuous and broad ChIP enrichment that might be too subtle to detect from ChIP peaks alone. The CEAS Python package is publicly available at http://liulab.dfci.harvard.edu/CEAS.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Pub. Group
                2041-1723
                28 May 2013
                : 4
                : 1908
                Affiliations
                [1 ]Division of Cell Biology, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [2 ]Central Genomic Facility, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [3 ]Division of Molecular Biology, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [4 ]Division of Diagnostic Oncology, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [5 ]Division of Molecular Pathology, The Netherlands Cancer Institute , Plesmanlaan 121, Amsterdam 1066CX, The Netherlands
                [6 ]Department of Hematology, VU University Medical Center , Boelelaan 1117, Amsterdam 1081 HV, The Netherlands
                [7 ]These authors contributed equally to this work
                Author notes
                Article
                ncomms2921
                10.1038/ncomms2921
                3674280
                23715267
                Copyright © 2013, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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