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

Cell Rep. 2021 Aug 31;36(9):109649. doi: 10.1016/j.celrep.2021.109649.

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.

Keywords: CAG instability; DNA repair; FAN1; FAN1 nuclease activity; GWAS; Huntington’s disease; MLH1; MSH3; mismatch repair; repeat expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / enzymology*
  • Brain / pathology
  • Cell Line, Tumor
  • DNA Damage*
  • DNA Mismatch Repair*
  • Endodeoxyribonucleases / genetics
  • Endodeoxyribonucleases / metabolism*
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • HEK293 Cells
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / enzymology*
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Mice
  • Multifunctional Enzymes / genetics
  • Multifunctional Enzymes / metabolism*
  • MutL Protein Homolog 1 / genetics
  • MutL Protein Homolog 1 / metabolism*
  • MutS Homolog 3 Protein / genetics
  • MutS Homolog 3 Protein / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Trinucleotide Repeat Expansion*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • MLH1 protein, human
  • MSH3 protein, human
  • Mlh1 protein, mouse
  • Multifunctional Enzymes
  • MutS Homolog 3 Protein
  • Endodeoxyribonucleases
  • Exodeoxyribonucleases
  • FAN1 protein, human
  • Fan1 protein, mouse
  • MutL Protein Homolog 1