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The Oncoprotein EVI1 and the DNA Methyltransferase Dnmt3 Co-Operate in Binding and De Novo Methylation of Target DNA

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Title: The Oncoprotein EVI1 and the DNA Methyltransferase Dnmt3 Co-Operate in Binding and De Novo Methylation of Target DNA
Author(s): Senyuk, Vitalyi; Premanand, Kavitha; Xu, Peng; Qian, Zhijian; Nucifora, Giuseppina
Subject(s): EVI1 methylation solid cancers
Abstract: EVI1 has pleiotropic functions during murine embryogenesis and its targeted disruption leads to prenatal death by severely affecting the development of virtually all embryonic organs. However, its functions in adult tissues are still unclear. When inappropriately expressed, EVI1 becomes one of the most aggressive oncogenes associated with human hematopoietic and solid cancers. The mechanisms by which EVI1 transforms normal cells are unknown, but we showed recently that EVI1 indirectly upregulates self-renewal and cell-cycling genes by inappropriate methylation of CpG dinucleotides in the regulatory regions of microRNA-124-3 (miR-124-3), leading to the repression of this small gene that controls normal differentiation and cell cycling of somatic cells. We used the regulatory regions of miR-124-3 as a read-out system to investigate how EVI1 induces de novo methylation of DNA. Here we show that EVI1 physically interacts with DNA methyltransferases 3a and 3b (Dnmt3a/b), which are the only de novo DNA methyltransferases identified to date in mouse and man, and that it forms an enzymatically active protein complex that induces de novo DNA methylation in vitro. This protein complex targets and binds to a precise region of miR-124-3 that is necessary for repression of a reporter gene by EVI1. Based on our findings, we propose that in cooperation with Dnmt3a/b EVI1 regulates the methylation of DNA as a sequence-specific mediator of de novo DNA methylation and that inappropriate EVI1 expression contributes to carcinogenesis through improper DNA methylation.
Issue Date: 2011-06-10
Publisher: Public Library of Science
Citation Info: Senyuk, V., Premanand, K., Xu, P., Qian, Z., & Nucifora, G. 2011. The Oncoprotein EVI1 and the DNA Methyltransferase Dnmt3 Co-Operate in Binding and De Novo Methylation of Target DNA. PLoS One, 6(6): e20793. DOI: 10.1371/journal.pone.0020793
Type: Article
Description: © 2011 Senyuk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The original version is available through the Public Library of Science at DOI: 10.1371/journal.pone.0020793.
URI: http://hdl.handle.net/10027/8370
ISSN: 1932-6203
Sponsor: This work was supported by National Institutes of Health (NIH) grants HL082935, HL079580, and CA096448 (GN).
Date Available in INDIGO: 2012-06-25
 

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