Modified oligonucleotides target the IRES in c-Myc to control gene expression

Abstract

Regulation of gene expression is attracting more attention as a means to develop gene
therapy for cancer, as it targets specifically cancer genes with no harm for healthy body
cells. Deregulation of c-Myc protein is found to occur in more than half of human tumours and correlates to aggressive cancer stages, with its resistance to therapy, making it very difficult to be cured by traditional cancer therapy. Controlling of gene expression could be a promising approach to regulate this oncoprotein, in particular, stopping the translation of the c-Myc mRNA.

Translation from mRNA to protein requires initiation, elongation and termination of the
peptide synthesis. Blocking the initiation factors, in particular binding of the ribosome to
the start site of mRNA, could be a way worth trying to stop translation.

The possible secondary structure of the c-Myc mRNA gives a potential new method to
control gene expression of mRNA. Apart from the common initiation sites, some mRNA
contains an internal ribosomal entry site (IRES) element, which is being better understood
in recent years. This could lead us to choose some more promising targets to control gene expression.

Oligonucleotides provide us a good resource to control the gene expression. Not only the
standard DNA, but in particular some modified oligonucleotides, including locked nucleic
acid (LNA) and phosphorothioate nucleic acid.

In this essay, we aimed to synthesise standard DNA and modified DNA, which target the
IRES point of the c-Myc gene to inhibit the translation process.

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Identifiers

ORCID for Eugen Stulz: orcid.org/0000-0002-5302-2276

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