Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation

• Published in: Nature communications Vol. 14; no. 1; pp. 99 - 17
• Main Authors: Esposito, Carla L., Autiero, Ida, Sandomenico, Annamaria, Li, H., Bassal, Mahmoud A., Ibba, Maria L., Wang, Dongfang, Rinaldi, Lucrezia, Ummarino, Simone, Gaggi, Giulia, Borchiellini, Marta, Swiderski, Piotr, Ruvo, Menotti, Catuogno, Silvia, Ebralidze, Alexander K., Kortylewski, Marcin, de Franciscis, Vittorio, Di Ruscio, Annalisa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.01.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 38/39; 38/47; 38/61; 38/77; 38/91; 631/208/200; 631/337/176/1988; 631/337/572; 631/61/391; 631/92/500; 64/60; 82/103; Aptamers; Cancer; Cell viability; Demethylation; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNMT1 protein; Epigenesis, Genetic; Epigenetics; Gene expression; Gene Expression Regulation, Neoplastic; Humanities and Social Sciences; Molecular modelling; multidisciplinary; Nucleic acids; Ribonucleic acid; RNA; RNA - genetics; RNA - metabolism; Science; Science (multidisciplinary); Side effects; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35222-4

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. Here the authors generate an RNA-based platform to neutralize the major epigenetic player DNMT1. Using this targeted approach, aberrant DNA methylation in cancer can be corrected.