Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis

Using unbiased CRISPRi screening, we found the loss of Fanconi anemia (FA) pathway proteins leads to deficiencies of lysosomal biology and autophagy. These defects are marked by dysregulation of TFEB, lysosomal membrane permeabilization, and a dependency on lysosomal exocytosis. Our findings are the first to link the FA pathway to major changes in lysosomal and autophagic state to a dependency on lysosomal exocytosis. Our findings expand our understanding of FA as a disease and of induced dependencies in FA mutant cancers.