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 oup.com
Nucleic Acids Researchoup.comOpen 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. 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.
The authors used parallel-binding TFOs with 6-amino-5-nitropyridin-2-one (Z). This base recognises G-C base pairs independently of pH. 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 oup.com
Nucleic Acids Researchoup.comOpen source ↗. Promoter activity fell by 50–80% in episomal reporter assays and at endogenous gene loci.
The strongest repression was seen at a GC-rich element that forms a quadruplex and acts as a structural hub for recruiting transcription factors. 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. They describe it as a general strategy for targeting GC-rich regulatory elements by programmable DNA recognition.
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.
