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

Carla L. Esposito (), Ida Autiero, Annamaria Sandomenico, H. Li, Mahmoud A. Bassal, Maria L. Ibba, Dongfang Wang, Lucrezia Rinaldi, Simone Ummarino, Giulia Gaggi, Marta Borchiellini, Piotr Swiderski, Menotti Ruvo, Silvia Catuogno, Alexander K. Ebralidze, Marcin Kortylewski (), Vittorio de Franciscis () and Annalisa Di Ruscio ()
Additional contact information
Carla L. Esposito: Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR
Ida Autiero: Molecular Horizon
Annamaria Sandomenico: Institute of Biostructures and Bioimaging, CNR
H. Li: City of Hope Medical Center
Mahmoud A. Bassal: National University of Singapore
Maria L. Ibba: Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR
Dongfang Wang: City of Hope National Medical Center
Lucrezia Rinaldi: Harvard Medical School
Simone Ummarino: Harvard Medical School
Giulia Gaggi: Harvard Medical School
Marta Borchiellini: University of Eastern Piedmont
Piotr Swiderski: City of Hope Medical Center
Menotti Ruvo: Institute of Biostructures and Bioimaging, CNR
Silvia Catuogno: Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR
Alexander K. Ebralidze: Harvard Medical School
Marcin Kortylewski: City of Hope National Medical Center
Vittorio de Franciscis: Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR
Annalisa Di Ruscio: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-35222-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35222-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-35222-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().