State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China.
University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Cell Rep. 2021 Feb 16;34(7):108713. doi: 10.1016/j.celrep.2021.108713.
AMP-activated protein kinase (AMPK) is an energy sensor that plays roles in multiple biological processes beyond metabolism. Several studies have suggested that AMPK is involved in the DNA damage response (DDR), but the mechanisms remain unclear. Herein, we demonstrate that AMPK promotes classic non-homologous end joining (c-NHEJ) in double-strand break (DSB) repair through recruiting a key chromatin-based mediator named p53-binding protein 1 (53BP1), which facilitates the end joining of distal DNA ends during DDR. We find that the interaction of AMPK and 53BP1 spatially occurs under DSB stress. In the context of DSBs, AMPK directly phosphorylates 53BP1 at Ser1317 and promotes 53BP1 recruitment during DDR for an efficient c-NHEJ, thus maintaining genomic stability and diversity of the immune repertoire. Taken together, our study demonstrates that AMPK is a regulator of 53BP1 and controls c-NHEJ choice by phospho-regulation.
AMP 激活的蛋白激酶 (AMPK) 是一种能量传感器，在代谢以外的多种生物学过程中发挥作用。有几项研究表明 AMPK 参与了 DNA 损伤反应 (DDR)，但其机制尚不清楚。本文中，我们证明 AMPK 通过招募一种称为 p53 结合蛋白 1（53BP1）的关键染色质中介体促进双链断裂 (DSB) 修复中的经典非同源末端连接 (c-NHEJ)，从而在 DDR 期间促进远端 DNA 末端的末端连接。我们发现 AMPK 和 53BP1 之间的相互作用在 DSB 应激下发生在空间上。在 DSB 情况下，AMPK 直接在 Ser1317 处磷酸化 53BP1，并在 DDR 期间促进 53BP1 的募集，以实现有效的 c-NHEJ，从而维持基因组稳定性和免疫库的多样性。总之，我们的研究表明 AMPK 是 53BP1 的调节剂，并通过磷酸化调节控制 c-NHEJ 的选择。
