Goold, R;
Hamilton, J;
Menneteau, T;
Flower, M;
Bunting, EL;
Aldous, SG;
Porro, A;
... Tabrizi, SJ; + view all
(2021)
FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
Cell Reports
, 36
(9)
, Article 109649. 10.1016/j.celrep.2021.109649.
Preview |
Text
1-s2.0-S2211124721010925-main.pdf - Published Version Download (3MB) | Preview |
Abstract
CAG repeat expansion in the HTT gene drives Huntington’s disease (HD) pathogenesis and is modulated by DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.
Archive Staff Only
 |
View Item |
