The Voice of the Chinese Academy of Sciences reported on February 26, 2021: Shanghai Institute of Materia Medica and others revealed a new mechanism for AMPK to promote DNA double-strand damage repair
On February 16, Li Jia and Zang Yi, researchers at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, published online research results titled AMPK-Mediated Phosphorylation on 53BP1 Promotes c-NHEJ on Cell Reports. This study provided an in-depth elucidation for the first time that AMPK promotes DNA double-strand damage repair and the specific mechanism. It was found that AMPK promotes c-NHEJ repair through the phosphorylation modification of the new substrate 53BP1, thereby maintaining the stability of the genome.
The protein kinase AMPK activated by adenosine monophosphate is an important energy sensor and regulator in cells, and plays an important role in regulating various life activities such as glucose and lipid metabolism, cell growth, cell polarity, cell mitosis and apoptosis. In recent years, there have been reports that AMPK may be involved in the important life process of DNA damage repair, but the specific mechanism of action is unknown.
DNA double-strand break (DSB, DNA double-strand break) is the most serious damage among all types of DNA damage, which can cause cell apoptosis and changes in chromosome structure. The regulation of DNA double-strand break repair (DSBR) is closely related to tumor development, tumor chemotherapy and tolerance. In this study, the biological function of AMPK was further investigated in this repair type. Studies have found that when DSB occurs, AMPKα2 catalytic subunits will be rapidly recruited to the damage site, and the knockout of AMPKα1/α2 dual catalytic subunits will cause a decrease in DSB repair efficiency and an increase in cell ionizing radiation sensitivity, which further confirms AMPK Participate in DSBR. In-depth study of the specific repair methods involved, researchers found that the loss of AMPKα catalytic subunits will lead to a decrease in the repair activity of non-homologous end joining (c-NHEJ), and the class of antibodies that depend on c-NHEJ during the maturation of B cells Defects of Conversion and Reorganization (CSR). In further study of the mechanism, it was found that AMPK can regulate the key protein 53BP1 in DSB damage repair through phosphorylation, promote its stable aggregation at the damage modification site H4K20me2, and recruit the downstream effector protein RIF1 to initiate the pathway. This phosphorylation regulation is promoting Play an important role in the completion of repair and maintaining the stability of the genome. This study revealed a new mechanism for AMPK to participate in the regulation of DNA damage and repair, and enriched the downstream regulatory network of AMPK and the upstream modification and regulation of 53BP1, which will help to further explore the relationship between AMPK in energy metabolism and DNA damage and repair.
Doctoral students Jiang Yuejing and Dong Ying of the Shanghai Institute of Materia Medica are the co-first authors of the paper, and the Shanghai Institute of Materia Medica is the first to complete the study. The research was assisted by Meng Feilong, a researcher at the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Tan Minjia and Huang Min, researchers at the Shanghai Institute of Materia Medica, and Huang Jun, a professor at Zhejiang University. The research work was funded by the National Natural Science Foundation of China, the National Science Fund for Distinguished Young Scholars, the Shanghai "Science and Technology Innovation Action Plan" and the Wang Kuancheng Talent Award of the Chinese Academy of Sciences.
Figure 1. AMPK is recruited to DSB sites and promotes c-NHEJ repair
Figure 2. AMPK-mediated phosphorylation of 53BP1-Ser1317 promotes DNA damage repair and genome stability
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