Instability of (CTG)(n)•(CAG)(n )trinucleotide repeats and DNA synthesis

Expansion of (CTG)(n)•(CAG)(n )trinucleotide repeat (TNR) microsatellite sequences is the cause of more than a dozen human neurodegenerative diseases. (CTG)(n )and (CAG)(n )repeats form imperfectly base paired hairpins that tend to expand in vivo in a length-dependent manner. Yeast, mouse and human models confirm that (CTG)(n)•(CAG)(n )instability increases with repeat number, and implicate both DNA replication and DNA damage response mechanisms in (CTG)(n)•(CAG)(n )TNR expansion and contraction. Mutation and knockdown models that abrogate the expression of individual genes might also mask more subtle, cumulative effects of multiple additional pathways on (CTG)(n)•(CAG)(n )instability in whole animals. The identification of second site genetic modifiers may help to explain the variability of (CTG)(n)•(CAG)(n )TNR instability patterns between tissues and individuals, and offer opportunities for prognosis and treatment.