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

Author

Listed:
  • Carla L. Esposito

    (Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR)

  • Ida Autiero

    (Molecular Horizon
    Institute of Biostructures and Bioimaging, CNR)

  • Annamaria Sandomenico

    (Institute of Biostructures and Bioimaging, CNR)

  • H. Li

    (City of Hope Medical Center)

  • Mahmoud A. Bassal

    (National University of Singapore
    Harvard Medical School)

  • 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
    Harvard Medical School)

  • Giulia Gaggi

    (Harvard Medical School)

  • Marta Borchiellini

    (University of Eastern Piedmont
    University of Eastern Piedmont)

  • Piotr Swiderski

    (City of Hope Medical Center)

  • Menotti Ruvo

    (Institute of Biostructures and Bioimaging, CNR
    Anbition srl)

  • Silvia Catuogno

    (Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR)

  • Alexander K. Ebralidze

    (Harvard Medical School
    Harvard Medical School)

  • Marcin Kortylewski

    (City of Hope National Medical Center)

  • Vittorio de Franciscis

    (Institute for Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), CNR
    Institute of Genetic and Biomedical Research (IRGB), CNR)

  • Annalisa Di Ruscio

    (Harvard Medical School
    University of Eastern Piedmont
    Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston)

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.

Suggested Citation

  • 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 Swi, 2023. "Targeted systematic evolution of an RNA platform neutralizing DNMT1 function and controlling DNA methylation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35222-4
    DOI: 10.1038/s41467-022-35222-4
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    References listed on IDEAS

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    1. Katherine E. Savell & Nancy V. N. Gallus & Rhiana C. Simon & Jordan A. Brown & Jasmin S. Revanna & Mary Katherine Osborn & Esther Y. Song & John J. O’Malley & Christian T. Stackhouse & Allison Norvil , 2016. "Extra-coding RNAs regulate neuronal DNA methylation dynamics," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    2. Marc Parisien & François Major, 2008. "The MC-Fold and MC-Sym pipeline infers RNA structure from sequence data," Nature, Nature, vol. 452(7183), pages 51-55, March.
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