FAN1-MLH1 interaction affects repair of DNA interstrand cross-links and slipped-CAG/CTG repeats.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
19
11
2020
accepted:
15
06
2021
entrez:
31
7
2021
pubmed:
1
8
2021
medline:
16
4
2022
Statut:
epublish
Résumé
FAN1, a DNA structure-specific nuclease, interacts with MLH1, but the repair pathways in which this complex acts are unknown. FAN1 processes DNA interstrand crosslinks (ICLs) and FAN1 variants are modifiers of the neurodegenerative Huntington's disease (HD), presumably by regulating HD-causing CAG repeat expansions. Here, we identify specific amino acid residues in two adjacent FAN1 motifs that are critical for MLH1 binding. Disruption of the FAN1-MLH1 interaction confers cellular hypersensitivity to ICL damage and defective repair of CAG/CTG slip-outs, intermediates of repeat expansion mutations. FAN1-S126 phosphorylation, which hinders FAN1-MLH1 association, is cell cycle-regulated by cyclin-dependent kinase activity and attenuated upon ICL induction. Our data highlight the FAN1-MLH1 complex as a phosphorylation-regulated determinant of ICL response and repeat stability, opening novel paths to modify cancer and neurodegeneration.
Identifiants
pubmed: 34330701
pii: 7/31/eabf7906
doi: 10.1126/sciadv.abf7906
pmc: PMC8324060
pii:
doi:
Substances chimiques
Multifunctional Enzymes
0
DNA
9007-49-2
Endodeoxyribonucleases
EC 3.1.-
Exodeoxyribonucleases
EC 3.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 714326
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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