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

Cell Rep. 2021-08; 
Robert Goold, Joseph Hamilton, Thomas Menneteau, Michael Flower, Emma L Bunting, Sarah G Aldous, Antonio Porro, José R Vicente, Nicholas D Allen, Hilary Wilkinson, Gillian P Bates, Alessandro A Sartori, Konstantinos Thalassinos, Gabriel Balmus, Sarah J Tabrizi
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Mutant Libraries Peptide competition assay Custom-designed FAN1 60-mer wild-type and MLH1-interaction-defective mutant peptides (amino acids 118-177) were purchased from GenScript (A.P., unpublished data). Get A Quote

摘要

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. The... More

关键词

CAG instability, DNA repair, FAN1, FAN1 nuclease activity, GWAS, Huntington’s disease, MLH1, MSH3, mismatch repair, repeat expansion