University of Portsmouth: Z-modified triplex-forming DNA cuts MYC promoter activity by 50–80%
Triplex-forming oligonucleotides with the synthetic base Z bound GC-rich MYC promoter elements and reduced promoter activity in laboratory experiments, the authors report.
A team led by Dr David Rusling at the University of Portsmouth has shown that triplex-forming oligonucleotides (TFOs) carrying the synthetic nucleobase Z reduce the activity of the MYC gene promoter by 50–80% in laboratory experiments. The work was published in Nucleic Acids Research in October 2026 doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. MYC is a gene associated with the growth of many cancers when it is overactive.
Why GC-rich DNA is hard to target
GC-rich gene regions are difficult to address because of their high duplex stability, repetitive sequences and tendency to form alternative DNA structures doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. TFOs are programmable molecules that recognise specific DNA sequences. However, natural nucleobases recognise G-C base pairs poorly in a cellular setting, which has limited the use of TFOs
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Nucleic Acids Researchdoi.orgOpen source ↗.
The authors used parallel-binding TFOs with 6-amino-5-nitropyridin-2-one (Z). This base recognises G-C base pairs independently of pH doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. According to the University of Portsmouth, Z is commercially available, so laboratories do not need to synthesise it themselves.
Results at the MYC promoter
The researchers chose two structurally distinct regulatory elements in the MYC promoter. Z-modified TFOs formed stable, sequence-selective triplexes on both doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. Promoter activity fell by 50–80% in episomal reporter assays and at endogenous gene loci
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Nucleic Acids Researchdoi.orgOpen source ↗.
The strongest repression was seen at a GC-rich element that forms a quadruplex and acts as a structural hub for recruiting transcription factors doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. According to the University, the modified molecules outperformed unmodified DNA and several earlier approaches aimed at the same regions.
The authors state that this is the first demonstration that a nucleobase modification alone allows parallel-binding TFOs to repress an endogenous gene doi.org
Nucleic Acids Researchdoi.orgOpen source ↗. They describe it as a general strategy for targeting GC-rich regulatory elements by programmable DNA recognition
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Nucleic Acids Researchdoi.orgOpen source ↗.
Rusling said that most drugs act on proteins, whereas targeting DNA works at the start of the process, and that each cell has only two copies of a gene. The University notes that the molecules could also serve as a research tool for temporarily switching off individual genes. It adds that further research is needed before the technology could be used in patients.
