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

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.