FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
View / Open Files
Authors
Goold, Robert
Hamilton, Joseph
Menneteau, Thomas
Flower, Michael
Bunting, Emma L
Aldous, Sarah G
Porro, Antonio
Vicente, José R
Allen, Nicholas D
Wilkinson, Hilary
Bates, Gillian P
Sartori, Alessandro A
Thalassinos, Konstantinos
Tabrizi, Sarah J
Publication Date
2021-08-31Journal Title
Cell Rep
ISSN
2211-1247
Publisher
Elsevier BV
Volume
36
Issue
9
Pages
109649
Language
eng
Type
Article
This Version
VoR
Physical Medium
Print
Metadata
Show full item recordCitation
Goold, R., Hamilton, J., Menneteau, T., Flower, M., Bunting, E. L., Aldous, S. G., Porro, A., et al. (2021). FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.. Cell Rep, 36 (9), 109649. https://doi.org/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.
Sponsorship
Medical Research Council (MR/L023784/2)
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2021.109649
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330058
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk