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

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

doi:10.1016/j.celrep.2021.109649

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.

Authors

Affiliations

¹ UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1N 3BG, UK.
² UK Dementia Research Institute, University College London, London WC1N 3BG, UK; Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
³ UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
⁴ Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
⁵ UK Dementia Research Institute, University of Cambridge, Cambridge CB2 0AH, UK.
⁶ School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
⁷ CHDI Management/CHDI Foundation, Princeton, NJ 08540, USA.
⁸ Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK; Institute of Structural and Molecular Biology, Birkbeck College, University of London, London WC1E 7HX, UK.
⁹ UK Dementia Research Institute, University of Cambridge, Cambridge CB2 0AH, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0AH, UK. Electronic address: gb318@cam.ac.uk.
¹⁰ UCL Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1N 3BG, UK. Electronic address: s.tabrizi@ucl.ac.uk.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding