ANKLE1 digests mitochondrial DNA and contributes to cancer risk by driving the Warburg effect and apoptosis resistance

Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of the ANKLE1 gene. ANKLE1 is molecularly characterized as an endonuclease that shuttles between the nucleus and cytoplasm and efficiently cuts branched DNA. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1's role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) digestion. mtDNA cleavage then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causative gene in the chr19p13.1 locus and provides mechanisms by which higher ANKLE1 expression promotes cancer risk. RNA-seq on 22 samples; control pEGFP-C1 or pEGFP-C1-ANKLE1 overexpressing HEK293T cells; 1, 3 and 7 days after transfection; 4 biological replicates each for Day 1; 4 biological replicates each for Day 3; 3 biological replicates each for Day 7