Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene. Repeat
length can change over time, both in individual cells and between generations, and
longer repeats may drive pathology. Cellular DNA repair systems have long been implicated
in CAG repeat instability but recent genetic evidence from humans linking DNA repair
variants to HD onset and progression has reignited interest in this area. The DNA
damage response plays an essential role in maintaining genome stability, but may also
license repeat expansions in the context of HD. In this chapter we summarize the methods
developed to assay CAG repeat expansion/contraction in vitro and in cells, and review
the DNA repair genes tested in mouse models of HD. While none of these systems is
currently ideal, new technologies, such as long-read DNA sequencing, should improve
the sensitivity of assays to assess the effects of DNA repair pathways in HD. Improved
assays will be essential precursors to high-throughput testing of small molecules
that can alter specific steps in DNA repair pathways and perhaps ameliorate expansion
or enhance contraction of the HTT CAG repeat.
