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dc.contributor.authorGoold, Robert
dc.contributor.authorHamilton, Joseph
dc.contributor.authorMenneteau, Thomas
dc.contributor.authorFlower, Michael
dc.contributor.authorBunting, Emma L
dc.contributor.authorAldous, Sarah G
dc.contributor.authorPorro, Antonio
dc.contributor.authorVicente, José R
dc.contributor.authorAllen, Nicholas D
dc.contributor.authorWilkinson, Hilary
dc.contributor.authorBates, Gillian P
dc.contributor.authorSartori, Alessandro A
dc.contributor.authorThalassinos, Konstantinos
dc.contributor.authorBalmus, Gabriel
dc.contributor.authorTabrizi, Sarah J
dc.date.accessioned2021-10-29T23:30:40Z
dc.date.available2021-10-29T23:30:40Z
dc.date.issued2021-08-31
dc.identifier.issn2211-1247
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330058
dc.description.abstractCAG 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.
dc.format.mediumPrint
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleFAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
dc.typeArticle
prism.issueIdentifier9
prism.publicationDate2021
prism.publicationNameCell Rep
prism.startingPage109649
prism.volume36
dc.identifier.doi10.17863/CAM.77502
dcterms.dateAccepted2021-08-11
rioxxterms.versionofrecord10.1016/j.celrep.2021.109649
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-08
dc.contributor.orcidBalmus, Gabriel [0000-0003-2872-4468]
dc.identifier.eissn2211-1247
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/L023784/2)
cam.issuedOnline2021-08-31


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International