A small unstructured nucleic acid disrupts a trinucleotide repeat hairpin

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Trinucleotide repeat (TNR) expansions are linked to numerous neurodegenerative disorders.
• TNR sequences can form non-canonical hairpin structures that facilitate their expansion during DNA replication and repair.
• Disrupting these TNR hairpins via strand invasion presents a potential therapeutic strategy.

Purpose of the Study:

• To investigate the ability of an unstructured nucleic acid, (CTG)(3), to invade and disrupt a (CAG)(10) TNR hairpin.
• To explore the potential of using unstructured nucleic acids as a scaffold for designing agents to prevent TNR expansion.

Main Methods:

• Utilized fluorescence, optical, and electrophoretic methods to observe the interaction between (CTG)(3) and a (CAG)(10) TNR hairpin.
• Analyzed the formation of duplex-like species resulting from the strand invasion.

Main Results:

• Demonstrated instantaneous disruption of the (CAG)(10) TNR hairpin by (CTG)(3) at low temperatures.
• Identified three distinct duplex-like species formed by the hybridization of one, two, or three (CTG)(3) sequences to the (CAG)(10) hairpin.
• (CTG)(3) was confirmed as an effective invader of the TNR hairpin structure.

Conclusions:

• Unstructured nucleic acids, exemplified by (CTG)(3), can effectively invade and disrupt TNR hairpins.
• These findings support the development of unstructured nucleic acids as a novel therapeutic approach to prevent TNR expansion in neurodegenerative diseases.