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

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 ar...

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Vydáno v:	Nature communications Ročník 4; číslo 1; s. 1908
Hlavní autoři:	Pang, Baoxu, Qiao, Xiaohang, Janssen, Lennert, Velds, Arno, Groothuis, Tom, Kerkhoven, Ron, Nieuwland, Marja, Ovaa, Huib, Rottenberg, Sven, van Tellingen, Olaf, Janssen, Jeroen, Huijgens, Peter, Zwart, Wilbert, Neefjes, Jacques
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 28.05.2013 Nature Publishing Group Nature Pub. Group
Témata:	631/154/436/2388 631/67/1059/99 Aclarubicin - chemistry Aclarubicin - pharmacology Animals Anthracyclines - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Apoptosis - drug effects Blast Crisis Cell Line, Tumor Cell Survival - drug effects Chromatin - chemistry Chromatin - metabolism Deoxyribonucleic acid DNA DNA - metabolism DNA Damage Doxorubicin - chemistry Doxorubicin - pharmacology Etoposide - chemistry Etoposide - pharmacology Heart - drug effects Histones - metabolism Humanities and Social Sciences Humans Intercalating Agents - pharmacology Leukemia Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Mice Mice, Nude multidisciplinary Nucleic Acid Conformation Nucleosomes - drug effects Nucleosomes - metabolism Organ Specificity - drug effects Science Science (multidisciplinary) Side effects Transcriptome - genetics
ISSN:	2041-1723, 2041-1723
On-line přístup:	Získat plný text
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Shrnutí:	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. 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 content type line 14 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms2921