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Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/30778

Title: The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA
Authors: López de Silanes, Isabel
Gorospe, Myriam
Taniguchi, Hiroaki
Abdelmohsen, Kotb
Srikantan, Subramanya
Alaminos Mingorance, Miguel
Berdasco, María
Urdinguio, Rocío G.
Fraga, Mario F.
Jacinto, Filipe v.
Esteller, Manel
Issue Date: 2009
Abstract: The molecular basis underlying the aberrant DNA-methylation patterns in human cancer is largely unknown. Altered DNA methyltransferase (DNMT) activity is believed to contribute, as DNMT expression levels increase during tumorigenesis. Here, we present evidence that the expression of DNMT3b is post-transcriptionally regulated by HuR, an RNA-binding protein that stabilizes and/or modulates the translation of target mRNAs. The presence of a putative HuR-recognition motif in the DNMT3b 3′UTR prompted studies to investigate if this transcript associated with HuR. The interaction between HuR and DNMT3b mRNA was studied by immunoprecipitation of endogenous HuR ribonucleoprotein complexes followed by RT–qPCR detection of DNMT3b mRNA, and by in vitro pulldown of biotinylated DNMT3b RNAs followed by western blotting detection of HuR. These studies revealed that binding of HuR stabilized the DNMT3b mRNA and increased DNMT3b expression. Unexpectedly, cisplatin treatment triggered the dissociation of the [HuR-DNMT3b mRNA] complex, in turn promoting DNMT3b mRNA decay, decreasing DNMT3b abundance, and lowering the methylation of repeated sequences and global DNA methylation. In summary, our data identify DNMT3b mRNA as a novel HuR target, present evidence that HuR affects DNMT3b expression levels post-transcriptionally, and reveal the functional consequences of the HuR-regulated DNMT3b upon DNA methylation patterns.
Sponsorship: Grants SAF2007-00027-65134; Consolider CSD2006-49; CANCERDIP FP7-200620; Spanish Ramon & Cajal Programme and the FIS Programme (PI061653) both from the Spanish Ministry of Science and Innovation (to I.L.S.). National Institute on Aging-IRP, National Institutes of Health (to M.G. and K.A.). Funding for open access charge: Fondo de Investigaciones Sanitarias (FIS). Spanish Ministry of Science and Innovation.
Publisher: Oxford University Press
Keywords: Cell line
Tumor
Antigens
Surface
Antineoplastic agents
RNA
Molecular sequence data
URI: http://hdl.handle.net/10481/30778
ISSN: 1362-4962
0305-1048
Rights : Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License
Citation: López de Silanes, I.; et al. The RNA-binding protein HuR regulates DNA methylation through stabilization of DNMT3b mRNA. Nucleic Acids Research, 37(8): 2658-2671 (2009). [http://hdl.handle.net/10481/30778]
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