Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
Department of Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, VA, USA.
Commun Biol. 2023 Mar 1;6(1):231. doi: 10.1038/s42003-023-04611-w.
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.
19p13.1 染色体位置上的等位基因与卵巢癌和乳腺癌风险增加以及 ANKLE1 基因表达增加有关。ANKLE1 作为一种分子内切酶，能够高效地切割分支 DNA，并在核和细胞质之间穿梭。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 的表达仅限于红系细胞系，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。我们表明，在乳腺上皮源性细胞中异位表达 ANKLE1 会导致基因组不稳定和线粒体 DNA（mtDNA）切割。mtDNA 的降解随后导致自噬，并导致氧化磷酸化向糖酵解（Warburg 效应）的转变。此外，mtDNA 的降解会激活 STAT1 和上皮-间充质转化（EMT）基因的表达。线粒体含量的减少导致抗凋亡，这可能使癌前细胞避免凋亡检查点并增殖。这些发现为 ANKLE1 是 19p13.1 染色体上的致癌易感性基因提供了证据，并描述了更高的 ANKLE1 表达如何促进癌症风险的机制。
