FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease
| Autor: | Alessandro A. Sartori, Gabriel Balmus, Gillian P. Bates, Konstantinos Thalassinos, Hilary Wilkinson, Joseph Hamilton, Michael Flower, Robert Goold, Emma L. Bunting, Antonio Porro, Sarah G. Aldous, Thomas Menneteau, Jose R. Vicente, Sarah J. Tabrizi, Nicholas D. Allen |
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| Přispěvatelé: | Balmus, Gabriel [0000-0003-2872-4468], Apollo - University of Cambridge Repository, University of Zurich, Balmus, Gabriel, Tabrizi, Sarah J, Menneteau, Thomas [0000-0003-1831-5425], Tabrizi, Sarah J [0000-0003-2716-2045] |
| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Mismatch repair complex DNA repair Context (language use) 610 Medicine & health Binding Competitive DNA Mismatch Repair General Biochemistry Genetics and Molecular Biology Article Mismatch repair Mice 1300 General Biochemistry Genetics and Molecular Biology Fan1 Cell Line Tumor Huntington’s Disease Animals Humans Protein Interaction Domains and Motifs Fan1 Nuclease Activity Nuclease Huntingtin Protein Endodeoxyribonucleases biology FAN1 10061 Institute of Molecular Cancer Research MLH1 Brain Msh3 Multifunctional Enzymes Cell biology Exodeoxyribonucleases HEK293 Cells Huntington Disease MSH3 Cag Instability MutS Homolog 3 Protein biology.protein 570 Life sciences Repeat Expansion DNA mismatch repair Trinucleotide repeat expansion MutL Protein Homolog 1 Trinucleotide Repeat Expansion DNA Damage Protein Binding Gwas |
| Zdroj: | Cell Reports |
| ISSN: | 2211-1247 |
| DOI: | 10.17863/cam.76364 |
| Popis: | Summary 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. Graphical abstract Highlights • FAN1 binds MLH1 via conserved 126SPYF129 residues, acting as a canonical MIP-box • FAN1-MLH1 binding regulates mismatch repair activity and complex formation • FAN1-MLH1 binding regulates the HTT CAG expansion rate FAN1 modifies Huntington’s disease pathogenesis, but the mechanism has remained elusive. Goold et al. demonstrate that FAN1 binds MLH1 through residues 126SPYF129, competing with MSH3, and sequesters MLH1 from the mismatch repair pathway. In turn, this reduces mismatch repair activity and suppresses expansion of the pathogenic HTT CAG trinucleotide repeat. |
| Databáze: | OpenAIRE |
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