FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
Bunting, Emma L
Aldous, Sarah G
Vicente, José R
Allen, Nicholas D
Bates, Gillian P
Sartori, Alessandro A
Tabrizi, Sarah J
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Goold, R., Hamilton, J., Menneteau, T., Flower, M., Bunting, E. L., Aldous, S. G., Porro, A., et al. (2021). FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.. Cell Rep, 36 (9), 109649. https://doi.org/10.1016/j.celrep.2021.109649
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.
External DOI: https://doi.org/10.1016/j.celrep.2021.109649
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330058
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/