Researchers Discover Novel Mechanisms of AMPK Promoting DNA Damage Repair

The adenosine 5’monophosphate-activated protein kinase (AMPK), as an important cellular energy sensor and regulator, plays roles in diverse cellular activities including glucose and lipid metabolism, cell growth, cell polarity, cell mitosis and apoptosis. Recently a few reports have demonstrated that AMPK might participate in regulation of DNA damage repair, but the detailed molecular mechanism was not yet fully understood.
To meet this challenge, scientists from the Li Jia group of Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences have discovered the novel and direct mechanisms of AMPK promoting DNA damage repair. This research was recently published online in Cell Reports.

 
Among all types of DNA damages, DNA double-strand break (DSB) are the most severe type, which is closely correlated with cell death and genomic stability, as well as tumor development and drug resistance. To further investigate the regulatory roles of AMPK in DSB repair, we found that AMPK α2 subunit was rapidly recruited to the damage site when DSB occurred, and the knockout of AMPK α1/α2 resulted in the decrease of DNA double strand break repair efficiency and the enhancement of cell sensitivity to ionizing radiation, which further confirmed that AMPK was involved in the DNA damage repair process. Then, we further studied the repair pathway choice of AMPK, and found that the deletion of AMPK would lead to the deficiency of c-NHEJ repair and the defect of NHEJ dependent class switching recombination (CSR) during activation of mature naive B cells. Further mechanism study found that AMPK phosphorylated the key protein 53BP1 in DSB damage repair and promoted 53BP1 binding to the accessible histone marker and downstream effector protein RIF1 pathway. Taken together, AMPK-53BP1 axis plays an important role in promoting efficient c-NHEJ during DDR, thus maintaining genomic stability and diversity of immune repertoire.
This study not only revealed the new mechanism of AMPK on DNA damage repair, but also enriched the downstream regulatory network of AMPK and the upstream regulation of 53BP1, which inspired us to further explore the relationship between AMPK in energy metabolism and DNA damage repair.
This work is supported by the National Natural Science Foundation of China, the National Science Fund for Distinguished Young Scholars, Shanghai Science and Technology Development Funds, and K. C. Wong Education Foundation.
Contact: Yi Zang, yzang@simm.ac.cn, Tel: 86-13681970322; Jia Li, jli@simm.ac.cn, Tel: +86-21-50801313 ext 132.
Full text: https://doi.org/10.1016/j.celrep.2021.108713.