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.
Keywords: CAG repeat; Cell models; DNA damage response; DNA repair; Genetic modifiers; Huntington’s disease; Mouse models; Neurodegeneration; Somatic expansion; Trinucleotide repeat.