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

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.

An alternative miRISC targets a cancer‐associated coding sequence mutation in FOXL2

“…However, the etiological nature of the 402C>G mutation remains largely unknown. Previously, we showed that the FOXL2 protein acts as a tumor suppressor and directs DNA double‐strand repair pathways in granulosa cells, whereas C134W FOXL2 was defective due to accelerated MDM2‐mediated ubiquitination and proteasomal degradation (Kim et al , 2011; Kim et al , 2014; Jin et al , 2020). However, a relatively moderate change in FOXL2 protein stability by the C134W mutation does not appear to wholly account for haploinsufficiency of the mutant FOXL2 (Kim et al , 2011; Kim et al , 2014).…”

Anticancer activity and metabolic profile alterations by ortho‐topolin riboside in in vitro and in vivo models of non‐small cell lung cancer

“…The immunoblot analysis was carried according to a previously described method. 32 In brief, A549 cells (4 × 10 5 ) were grown to approximately 70%-80% confluency and treated with increasing concentrations of oTR (5, 10, and 50 μM) for 48 h. The cell lysates and tissue lysates were prepared and subjected to SDS-PAGE for immunoblotting with the respective antibodies. Anti-Caspase-3 (9662), anti-p-AKT (4058), and anti-AKT (9272) antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA).…”

Predictable increase in female reproductive window: A simple model connecting age of reproduction, menopause, and longevity

“…For instance, estrogens influence meiosis resumption in pre-ovulatory oocytes in mammals [59] or FOXL2, a classical transcription factor, is known to direct double strand break repair pathway by direct binding the complex Ku (XRCC5/6). [60] In the light of the strong genetic component of human fertility, it is interesting to reflect on how the evolution of the socio-economic environment can impact on the genetic make-up of human populations.…”

“…For instance, estrogens influence meiosis resumption in pre‐ovulatory oocytes in mammals [ 59 ] or FOXL2, a classical transcription factor, is known to direct double strand break repair pathway by direct binding the complex Ku (XRCC5/6). [ 60 ]…”