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

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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)

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.

Suggested Citation

  • 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 & Jeehyeon Bae, 2020. "FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15748-1
    DOI: 10.1038/s41467-020-15748-1
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