Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation(89 views) Esposito CL, Autiero I, Sandomenico A, Li H, Bassal MA, Ibba ML, Wang D, Rinaldi L, Ummarino S, Gaggi G, Borchiellini M, Swiderski P, Ruvo M, Catuogno S, Ebralidze AK, Kortylewski M, De Franciscis V, Di Ruscio A
Paper type: Journal Article
, Research Support, N. I. H. , Extramural
, Non-U. S. Gov'T
Impact factor: 0, 5-year impact factor: 0
Url: Not available.
Keywords: Dna Methylation
, Rna Genetics Metabolism
, Dna (cytosine-5-)-Methyltransferases Metabolism
, Gene Expression Regulation, Neoplastic
, Dna (cytosine-5-)-Methyltransferase 1 Genetics Metabolism
, Epigenesis
Affiliations: *** IBB - CNR ***
Institute for Experimental Endocrinology and Oncology "Gaetano Salvatore" (IEOS), CNR, Naples, 80100, Italy. c.esposito@ieos.cnr.it.
Molecular Horizon, Bettona (PG), 06084, Italy.
Institute of Biostructures and Bioimaging, CNR, Naples, 80100, Italy.
The Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, 91010, USA.
Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore, Singapore.
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, 02115, USA.
Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, 91010, USA.
Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA, 02115, USA.
Department of Translational Medicine, University of Eastern Piedmont, Novara, 28100, Italy.
Department of Health Sciences, University of Eastern Piedmont, Novara, 28100, Italy.
Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, 91010, USA.
Anbition srl, Naples, 80100, Italy.
Institute of Genetic and Biomedical Research (IRGB), CNR, Milan, 20090, Italy. vittorio.defranciscis@irgb.cnr.it.
Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, 330 Brookline Avenue Boston, Boston, MA, 02215, USA. adirusci@bidmc.harvard.edu.
References: Not available.
Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
DNA methylation is a fundamental epigenetic modification regulating gene expression. Aberrant DNA methylation is the most common molecular lesion in cancer cells. However, medical intervention has been limited to the use of broadly acting, small molecule-based demethylating drugs with significant side-effects and toxicities. To allow for targeted DNA demethylation, we integrated two nucleic acid-based approaches: DNMT1 interacting RNA (DiR) and RNA aptamer strategy. By combining the RNA inherent capabilities of inhibiting DNMT1 with an aptamer platform, we generated a first-in-class DNMT1-targeted approach - aptaDiR. Molecular modelling of RNA-DNMT1 complexes coupled with biochemical and cellular assays enabled the identification and characterization of aptaDiR. This RNA bio-drug is able to block DNA methylation, impair cancer cell viability and inhibit tumour growth in vivo. Collectively, we present an innovative RNA-based approach to modulate DNMT1 activity in cancer or diseases characterized by aberrant DNA methylation and suggest the first alternative strategy to overcome the limitations of currently approved non-specific hypomethylating protocols, which will greatly improve clinical intervention on DNA methylation.
Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(418 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote