AMPK-mediated phosphorylation on 53BP1 promotes c-NHEJ.

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.