FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku

Hanyong Jin, Boeun Lee, Yongyang Luo, Yuri Choi, Eui-Hwan Choi, Hong Jin, Kee-Beom Kim, Sang Beom Seo, Yong-Hak Kim, Hyung Ho Lee (), Keun Pil Kim (), Kangseok Lee () and Jeehyeon Bae ()
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Hanyong Jin: Chung-Ang University
Boeun Lee: Chung-Ang University
Yongyang Luo: Chung-Ang University
Yuri Choi: Seoul National University
Eui-Hwan Choi: Chung-Ang University
Hong Jin: Chung-Ang University
Kee-Beom Kim: Chung-Ang University
Sang Beom Seo: Chung-Ang University
Yong-Hak Kim: Catholic University of Daegu School of Medicine
Hyung Ho Lee: Seoul National University
Keun Pil Kim: Chung-Ang University
Kangseok Lee: Chung-Ang University
Jeehyeon Bae: Chung-Ang University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15748-1

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