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Published on: February 24, 2014
Energy Deficiency-Induced ATG4B Nuclear Translocation Inhibits PRMT1-Mediated DNA Repair and Promotes Leukemia
Zhenkun Wang1, Xianli Zhang1, Yuanyuan Zhou1,2
1Key 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.
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.
Insights
Energy deficiency disrupts DNA repair via ATG4B nuclear translocation, causing genomic instability. Inhibiting ATG4B enhances DNA repair and survival in acute myeloid leukemia (AML) models.
Area of Science:
- Molecular Biology
- Cancer Biology
- Metabolism
Background:
- Cancer is characterized by metabolic alterations and genomic instability.
- The links between metabolism and DNA repair are not fully understood.
- Understanding these links is crucial for developing new cancer therapies.
Purpose of the Study:
- To elucidate the molecular mechanism linking cellular energy metabolism and DNA repair.
- To investigate the role of ATG4B in regulating DNA repair during energy deficiency.
- To explore ATG4B as a therapeutic target in acute myeloid leukemia (AML).
Main Methods:
- Investigated the translocation of ATG4B during energy deficiency.
- Examined the interaction between ATG4B and PRMT1.
- Assessed the effect of ATG4B inhibition on DNA repair and AML progression in vitro and in vivo.
Main Results:
- Energy deficiency causes ATG4B to translocate to the nucleus, inhibiting DNA repair by disrupting PRMT1-mediated MRE11 methylation.
- This leads to genomic instability, particularly in acute myeloid leukemia (AML) cells.
- Inhibition of ATG4B in AML models improved DNA repair, reduced proliferation, decreased mutation burden, and prolonged survival.
Conclusions:
- Energy deficiency compromises DNA repair through ATG4B nuclear translocation.
- ATG4B inhibition represents a promising therapeutic strategy for AML by enhancing DNA repair and mitigating malignant evolution.
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