FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
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.
Mesh Terms:
Animals, Binding, Competitive, Brain, Cell Line, Tumor, DNA Damage, DNA Mismatch Repair, Endodeoxyribonucleases, Exodeoxyribonucleases, HEK293 Cells, Humans, Huntingtin Protein, Huntington Disease, Mice, Multifunctional Enzymes, MutL Protein Homolog 1, MutS Homolog 3 Protein, Protein Binding, Protein Interaction Domains and Motifs, Trinucleotide Repeat Expansion
Animals, Binding, Competitive, Brain, Cell Line, Tumor, DNA Damage, DNA Mismatch Repair, Endodeoxyribonucleases, Exodeoxyribonucleases, HEK293 Cells, Humans, Huntingtin Protein, Huntington Disease, Mice, Multifunctional Enzymes, MutL Protein Homolog 1, MutS Homolog 3 Protein, Protein Binding, Protein Interaction Domains and Motifs, Trinucleotide Repeat Expansion
Cell Rep
Date: Dec. 31, 2020
PubMed ID: 34469738
View in: Pubmed Google Scholar
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