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.
Highlights
The balance between major DNA double-strand break (DSB) repair pathways is influenced by binding of the Ku complex, a XRCC5/6 heterodimer, to Double-strand breaks (DSBs) ends, initiating non-homologous end joining (NHEJ) but preventing additional DSB end resection and homologous recombination (HR)
The key molecular event at DSB sites destined for either the NHEJ or the HR pathway is the recruitment of the heterodimeric Ku complex comprised of XRCC5 and XRCC6 to DSBs, which promotes NHEJ initiation and prevents additional DSB end resection that facilitates HR
Considering that XRCC5 and XRCC6 are very abundant in cells and their Ku heterodimer has a remarkably high binding affinity for DNA ends, a well-refined regulatory system that allows tight control of Ku complex recruitment to DSB regions for NHEJ must exist to avoid their random association with DSBs
Summary
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). Our study unveils the SIRT1-(de)acetylated FOXL2-Ku axis that governs the balance of DSB repair pathways to maintain genome integrity. NHEJ is rapid, robust, and the primary repair pathway before DNA replication occurs[5,6] It is error-prone and can result in the accumulation of somatic mutations that can cause cancer development and cellular abnormalities. The Ku complex acts as a key factor in balancing the DSB repair pathway, along with 53BP1, Rif[1], PTIP, and BRCA1, by blocking DSB end resection[2,10]. The pathogenic mechanisms of these FOXL2 mutations remain unclear
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