FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku.
Acetylation
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA End-Joining Repair
Forkhead Box Protein L2
/ genetics
HEK293 Cells
Homologous Recombination
Humans
Ku Autoantigen
/ genetics
Mutation
Protein Binding
/ genetics
RNA, Small Interfering
/ metabolism
Recombinant Proteins
/ genetics
Sirtuin 1
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 04 2020
24 04 2020
Historique:
received:
23
07
2019
accepted:
22
03
2020
entrez:
26
4
2020
pubmed:
26
4
2020
medline:
11
8
2020
Statut:
epublish
Résumé
The balance between major DNA double-strand break (DSB) repair pathways is influenced by binding of the Ku complex, a XRCC5/6 heterodimer, to DSB ends, initiating non-homologous end joining (NHEJ) but preventing additional DSB end resection and homologous recombination (HR). However, the key molecular cue for Ku recruitment to DSB sites is unknown. Here, we report that FOXL2, a forkhead family transcriptional factor, directs DSB repair pathway choice by acetylation-dependent binding to Ku. Upon DSB induction, SIRT1 translocates to the nucleus and deacetylates FOXL2 at lysine 124, leading to liberation of XRCC5 and XRCC6 from FOXL2 and formation of the Ku complex. FOXL2 ablation enhances Ku recruitment to DSB sites, imbalances DSB repair kinetics by accelerating NHEJ and inhibiting HR, and thus leads to catastrophic genomic events. Our study unveils the SIRT1-(de)acetylated FOXL2-Ku axis that governs the balance of DSB repair pathways to maintain genome integrity.
Identifiants
pubmed: 32332759
doi: 10.1038/s41467-020-15748-1
pii: 10.1038/s41467-020-15748-1
pmc: PMC7181608
doi:
Substances chimiques
FOXL2 protein, human
0
Forkhead Box Protein L2
0
RNA, Small Interfering
0
Recombinant Proteins
0
SIRT1 protein, human
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
XRCC5 protein, human
EC 3.6.4.12
Xrcc6 protein, human
EC 3.6.4.12
Ku Autoantigen
EC 4.2.99.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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