Chr19p13.1区域内的等位基因与卵巢癌和乳腺癌的风险增加以及ANKLE1基因表达增加有关。ANKLE1被分子特征化为一个高效剪切分支DNA并在细胞核和细胞质之间穿梭的内切酶。然而，ANKLE1在哺乳动物发育和稳态中的作用仍然未知。在正常发育中，ANKLE1表达仅限于红细胞前体细胞系，并且我们发现ANKLE1的作用是在红细胞生成过程中切割线粒体基因组。我们展示了ANKLE1在乳腺上皮细胞中过度表达导致了基因组不稳定和线粒体DNA(mtDNA)的裂解。mtDNA的降解然后导致线粒体自噬，并导致从氧化磷酸化转变为糖酵解（沃尔堡效应）。此外，mtDNA的降解激活STAT1和表皮间质转化（EMT）基因的表达。线粒体含量的降低有助于抗凋亡性的增加，这可能使癌前细胞避免凋亡检查点并增殖。这些发现提供了ANKLE1是chr19p13.1区域致癌易感基因的证据，并描述了更高的ANKLE1表达促进癌症风险的机制。 ©2023年作者。

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.© 2023. The Author(s).