FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease

Goold, Robert, Hamilton, Joseph, Menneteau, Thomas, Flower, Michael, Bunting, Emma L., Aldous, Sarah G., Porro, Antonio, Vicente, José R., Allen, Nicholas D. ORCID: https://orcid.org/0000-0003-4009-186X, Wilkinson, Hilary, Bates, Gillian P., Sartori, Alessandro A., Thalassinos, Konstantinos, Balmus, Gabriel and Tabrizi, Sarah J. 2021. FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease. Cell Reports 36 (9) , 109649. 10.1016/j.celrep.2021.109649

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Biosciences
Additional Information:	This is an open access article under the CC BY license
Publisher:	Cell Press
ISSN:	2211-1247
Date of First Compliant Deposit:	13 January 2022
Date of Acceptance:	11 August 2021
Last Modified:	24 Jul 2024 15:01
URI:	https://orca.cardiff.ac.uk/id/eprint/146584

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