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Repetitive DNA sequences within genes play a vital role in maintaining normal function and pathology. Abnormal increases in the number of repeating units, or expansion, of repetitive sequences have been associated with more than 30 different types of hereditary diseases. Among these, expansion of trinucleotide repeats (TNRs) are arguably the most important, accounting for at least 14 diseases including Huntington's and fragile X syndrome. Small molecules that bind to specific TNR DNA sequences could find application as diagnostic tools as well as therapeutic agents. Understanding how these compounds interact with TNR DNA should provide clues to their mechanisms of action and empower the development of novel therapeutics. Various biochemical and biophysical methods are required to elucidate the interaction between these compounds and TNR DNA. This chapter will summarize the different types of compounds that interact with abnormal trinucleotide repeat expansions in DNA. We will discuss their respective mechanisms in the light of experimental evidence, and discuss how this information can lead to potential applications.

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