Surveillance of aneuploidy by oxidative stress sensing through ATPAF1

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.