FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease.
Animals
Binding, Competitive
Brain
/ enzymology
Cell Line, Tumor
DNA Damage
DNA Mismatch Repair
Endodeoxyribonucleases
/ genetics
Exodeoxyribonucleases
/ genetics
HEK293 Cells
Humans
Huntingtin Protein
/ genetics
Huntington Disease
/ enzymology
Mice
Multifunctional Enzymes
/ genetics
MutL Protein Homolog 1
/ genetics
MutS Homolog 3 Protein
/ genetics
Protein Binding
Protein Interaction Domains and Motifs
Trinucleotide Repeat Expansion
CAG instability
DNA repair
FAN1
FAN1 nuclease activity
GWAS
Huntington’s disease
MLH1
MSH3
mismatch repair
repeat expansion
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
31 08 2021
31 08 2021
Historique:
received:
17
03
2021
revised:
30
06
2021
accepted:
11
08
2021
entrez:
1
9
2021
pubmed:
2
9
2021
medline:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34469738
pii: S2211-1247(21)01092-5
doi: 10.1016/j.celrep.2021.109649
pmc: PMC8424649
pii:
doi:
Substances chimiques
HTT protein, human
0
Huntingtin Protein
0
MLH1 protein, human
0
MSH3 protein, human
0
Mlh1 protein, mouse
0
Multifunctional Enzymes
0
MutS Homolog 3 Protein
0
Endodeoxyribonucleases
EC 3.1.-
Exodeoxyribonucleases
EC 3.1.-
FAN1 protein, human
EC 3.1.-
Fan1 protein, mouse
EC 3.1.-
MutL Protein Homolog 1
EC 3.6.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109649Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200181/Z/15/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A patent (application number 2105484.6) on the FAN1-MLH1 interaction and structural analogs for the treatment of disease has been filed by the University of Cambridge and UCL. The data presented in this patent are included in the main paper and supplemental information. G.B. is a co-founder and consultant for Adrestia Therapeutics. E.L.B. is the daughter of an advisor for Adrestia Therapeutics.
Références
Nat Biotechnol. 2012 Oct;30(10):918-20
pubmed: 23051804
PLoS Genet. 2013 Oct;9(10):e1003930
pubmed: 24204323
EMBO J. 2014 Aug 1;33(15):1698-712
pubmed: 24966277
Cancer Cell. 2021 Jan 11;39(1):109-121.e5
pubmed: 33338427
Hum Mol Genet. 2019 Feb 15;28(4):650-661
pubmed: 30358836
Nat Commun. 2011;2:281
pubmed: 21505437
Neuron. 2015 Nov 18;88(4):667-77
pubmed: 26590344
Mol Syst Biol. 2019 Sep;15(9):e8994
pubmed: 31556486
Science. 2020 Mar 6;367(6482):
pubmed: 32139519
Genes Cells. 2020 Mar;25(3):175-186
pubmed: 31955481
Mol Cell Biol. 2009 Feb;29(3):907-18
pubmed: 19015241
Hum Mol Genet. 2009 Aug 15;18(16):3039-47
pubmed: 19465745
Brain. 2019 Jun 19;:
pubmed: 31216018
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2366-70
pubmed: 23341618
Cell. 2006 Jul 28;126(2):239-41
pubmed: 16873053
Hum Mol Genet. 2011 Nov 15;20(22):4395-410
pubmed: 21865299
Nat Rev Neurol. 2020 Oct;16(10):529-546
pubmed: 32796930
Am J Hum Genet. 2020 Jul 2;107(1):96-110
pubmed: 32589923
Neuroepidemiology. 2016;46(2):144-53
pubmed: 26824438
Anal Chem. 2019 Feb 5;91(3):1808-1814
pubmed: 30620560
Hum Mol Genet. 2020 Nov 4;29(18):3044-3053
pubmed: 32876667
Brain Commun. 2020 Aug 03;2(2):fcaa066
pubmed: 32954323
Nat Struct Mol Biol. 2010 Aug;17(8):926-8
pubmed: 20683477
J Biol Chem. 2010 Apr 9;285(15):11730-9
pubmed: 20154325
Science. 1996 Aug 23;273(5278):1109-11
pubmed: 8688098
Mol Cell Biol. 2014 Nov;34(21):3939-54
pubmed: 25135477
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1091-101
pubmed: 15279797
Science. 2016 Feb 19;351(6275):846-9
pubmed: 26797144
PLoS Genet. 2013;9(2):e1003280
pubmed: 23468640
Nat Protoc. 2007;2(8):1896-906
pubmed: 17703201
Mol Cell. 2010 Jul 9;39(1):36-47
pubmed: 20603073
Cell. 2010 Jul 9;142(1):65-76
pubmed: 20603015
Curr Colorectal Cancer Rep. 2017 Feb;13(1):73-80
pubmed: 28367107
Nucleic Acids Res. 2019 Jan 8;47(D1):D442-D450
pubmed: 30395289
Mol Cell Proteomics. 2016 Mar;15(3):854-65
pubmed: 26560067
PLoS One. 2014 Oct 10;9(10):e109752
pubmed: 25303670
Cell. 2019 Aug 8;178(4):887-900.e14
pubmed: 31398342
PLoS Genet. 2020 Jun 26;16(6):e1008902
pubmed: 32589669
Am J Hum Genet. 2019 Jun 6;104(6):1116-1126
pubmed: 31104771
Nat Protoc. 2014 Jan;9(1):120-37
pubmed: 24356771
Nat Commun. 2014 Dec 11;5:5726
pubmed: 25500724
Lancet Neurol. 2020 Nov;19(11):930-939
pubmed: 33098802
J Med Genet. 1993 Dec;30(12):982-6
pubmed: 8133508
Nat Rev Dis Primers. 2015 Apr 23;1:15005
pubmed: 27188817
Sci Rep. 2017 May 2;7(1):1307
pubmed: 28465506