Targeting Pathogenic DNA and RNA Repeats: A Conceptual Therapeutic Way for Repeat Expansion Diseases

Expansions of short tandem repeats (STRs) in the human genome cause nearly 50 neurodegenerative diseases, which are mostly inheritable, nonpreventable and incurable, posing as a huge threat to human health. Non-B DNAs formed by STRs are thought to be structural intermediates that can cause repeat expansions. The subsequent transcripts harboring expanded RNA repeats can further induce cellular toxicity through forming specific structures. Direct targeting of these pathogenic DNA and RNA repeats has emerged as a new potential therapeutic strategy to cure repeat expansion diseases. In this conceptual review, we first introduce the roles of DNA and RNA structures in the genetic instabilities and pathomechanisms of repeat expansion diseases, then describe structural features of DNA and RNA repeats with a focus on the tertiary structures determined by X-ray crystallography and solution nuclear magnetic resonance spectroscopy, and finally discuss recent progress and perspectives of developing chemical tools that target pathogenic DNA and RNA repeats for curing repeat expansion diseases.