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journal article·2025-10Open access

Energy Deficiency‐Induced ATG4B Nuclear Translocation Inhibits PRMT1‐Mediated DNA Repair and Promotes Leukemia Progression

Zhenkun Wang, Xianli Zhang, Yuanyuan Zhou, Shuyi Lin, Yuting Fu, Haiping Liu, Qiongdan Gao, YanHong Xiao, Zhao Yin, Shuang Liu, Kexiu Huang, Suqi Deng, Juan Du, Hui Zeng, Jia Wang, Jinping Zheng, Qinghua Zhou, Tianfeng Chen, Xiaoling Gao, Zhenyu Ju, Bo Liu

Advanced Science· Volume 12· Issue 40
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Source abstract

Abstract

Abstract Metabolic alterations and genomic instability are the hallmark features of many cancers. However, the precise mechanisms underlying the intricate links among these processes remain largely unknown. Here, a molecular mechanism is presented that regulates the interplay between cellular energy metabolism and DNA repair. These findings demonstrate that during energy deficiency, ATG4B translocates from the cytoplasm to the nucleus and disrupts DNA repair by directly interacting with PRMT1. This interaction inhibits the PRMT1‐dependent methylation of MRE11, a key regulator of DNA repair, leading to genomic instability. Importantly, it is shown that ATG4B‐mediated DNA repair defects are significantly enhanced in patient‐derived acute myeloid leukemia (AML) cells and in mouse AML cells induced by MLLT3‐KMT2A overexpression. Inhibition of ATG4B enhanced PRMT1‐mediated DNA damage responses, suppressed cell proliferation, reduced the mutation burden, and prolonged survival in mice with MLLT3‐KMT2A‐induced AML and in those bearing AML patient‐derived xenografts. These findings revealed that energy deficiency compromises DNA repair through ATG4B nuclear translocation, and ATG4B inhibition enhances DNA repair in AML cells, alleviating the malignant evolution of AML.
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Research context

OpenAlex topics: Epigenetics and DNA Methylation · Acute Myeloid Leukemia Research · Genetics and Neurodevelopmental Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative Medicine College of Life Science and Technology Jinan University Guangzhou 510632 China

Shanxi Key Laboratory of Aging Mechanism Research and Translational Applications Changzhi Medical College Changzhi Shanxi 046000 China

Biomedical Innovation Center Department of Clinical Laboratory The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou 510655 China

Guangdong Second Provincial General Hospital Jinan university Guangzhou 510317 China

Department of Hematology The First Affiliated Hospital of Jinan University Guangzhou 510630 China

College of Life Science and Technology Jinan University Guangzhou 510632 China

Department of Chemistry Jinan University Guangzhou 510632 China

The clinical Laboratory Center Hainan General Hospital Hainan affiliated Hospital of Hainan Medical University Haikou 570311 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Basic and Applied Basic Research Foundation of Guangdong Province

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