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Surveillance of aneuploidy by oxidative stress sensing through ATPAF1

ABSTRACT: Aneuploidy, the aberrant number of chromosomes, is a major consequence of chromosomal instability (CIN) and a hallmark of cancer. Aneuploidy imposes significant fitness costs related to proteotoxic, replicative, mitotic, and metabolic stress. However, the molecular basis by which cellular surveillance systems sense these aneuploidy-associated stresses remains poorly understood. Using a genome-wide CRISPR-Cas9 screen, we identified ATPAF1 as a novel aneuploidy sensing gene. Loss of ATPAF1 confers proliferation advantage in CIN conditions and enriched aneuploid population by reducing apoptosis. Mechanistically, we establish a bidirectional relationship between aneuploidy onset and oxidative stress, revealing that ATPAF1 functions as a specific sensor for aneuploidy-associated reactive oxygen species. Our pan-cancer analysis demonstrates a positive correlation between the dysregulations of oxidative stress response pathways and increased aneuploidy severity, suggesting how cancer cells can actively reprogram oxidative stress responses to strive for survival despite CIN. Taken together, our work elucidates a novel mechanism of aneuploidy surveillance mediated by ATPAF1-dependent oxidative stress sensing, offering potential therapeutic targets or biomarkers for overcoming cancer aneuploidy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324019 | GEO | 2026/03/10

REPOSITORIES: GEO

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