Department of Life Science, Chung-Ang University, Seoul, 06974, Korea.
School of Pharmacy, Chung-Ang University, Seoul, 06974, Korea.
Nat Commun. 2020 Apr 24;11(1):2010. doi: 10.1038/s41467-020-15748-1.
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.
双链 DNA 断裂 (DSB) 修复途径之间的平衡受到 Ku 复合物的影响，Ku 复合物是一个 XRCC5/6 异二聚体，与 DSB 末端结合，启动非同源末端连接 (NHEJ)，但防止额外的 DSB 末端切除和同源重组 (HR)。然而，Ku 招募到 DSB 位点的关键分子线索尚不清楚。在这里，我们报告说，叉头框转录因子 FOXL2 通过依赖于乙酰化的与 Ku 的结合来指导 DSB 修复途径的选择。在 DSB 诱导后，SIRT1 易位到细胞核，并在赖氨酸 124 处去乙酰化 FOXL2，导致 XRCC5 和 XRCC6 从 FOXL2 中释放出来，并形成 Ku 复合物。FOXL2 的缺失增强了 Ku 招募到 DSB 位点，通过加速 NHEJ 和抑制 HR 来改变 DSB 修复动力学，从而导致灾难性的基因组事件。我们的研究揭示了 SIRT1-(去)乙酰化 FOXL2-Ku 轴，该轴控制 DSB 修复途径的平衡，以维持基因组完整性。
