ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation

Abstract

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 efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. 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) cleavage. mtDNA degradation 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 causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.

On The Origin of Speciation

“…ANKLE1 is normally expressed only in erythroblasts, but is also expressed in cancer and is associated with the risk of developing ovarian and breast cancers. Ectopic expression in mammary gland cells was shown to induce mitophagy through mtDNA degradation, shifting metabolism from oxidative phosphorylation to glycolysis (i.e., Warburg effect) (Warburg, 1956) and avoiding apoptosis (Przanowski et al, 2021).…”

Functional dissection of the conservedC. elegansLEM-3/ANKLE1 nuclease reveals a crucial requirement for the LEM-like and GIY-YIG domains for DNA bridges processing

“…All in all, vertebrate evolution might have prioritized ANKLE1 bridge cleavage to allow for cytokinesis, even if it is associated with a risk of chromosomal aberrations. In addition, ANKLE1 has been reported to function in mitochondrial DNA degradation, which occurs during erythrocyte differentiation (22). In contrast, the exquisite sensitivity of lem-3 mutant worms to various forms of DNA damage and the requirement for LEM-3 midbody localization for mending branched DNA intermediates suggest that C. elegans LEM-3 may be part of a mechanism that promotes genome integrity (9).…”