Huntington's disease (HD) is an inherited neurodegenerative disease caused by an 
expanded CAG repeat in the huntingtin (HTT) gene. CAG repeat length explains 
around half of the variation in age at onset (AAO) but genetic variation 
elsewhere in the genome accounts for a significant proportion of the remainder. 
Genome-wide association studies have identified a bidirectional signal on 
chromosome 15, likely underlain by FANCD2- and FANCI-associated nuclease 1 
(FAN1), a nuclease involved in DNA interstrand cross link repair. Here we show 
that increased FAN1 expression is significantly associated with delayed AAO and 
slower progression of HD, suggesting FAN1 is protective in the context of an 
expanded HTT CAG repeat. FAN1 overexpression in human cells reduces CAG repeat 
expansion in exogenously expressed mutant HTT exon 1, and in patient-derived 
stem cells and differentiated medium spiny neurons, FAN1 knockdown increases CAG 
repeat expansion. The stabilizing effects are FAN1 concentration and CAG repeat 
length-dependent. We show that FAN1 binds to the expanded HTT CAG repeat DNA and 
its nuclease activity is not required for protection against CAG repeat 
expansion. These data shed new mechanistic insights into how the genetic 
modifiers of HD act to alter disease progression and show that FAN1 affects 
somatic expansion of the CAG repeat through a nuclease-independent mechanism. 
This provides new avenues for therapeutic interventions in HD and potentially 
other triplet repeat disorders.