ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation.
ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation.
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Ankle1裂解线粒体DNA，并通过促进凋亡耐药性和代谢失调来促进癌症风险。
DOI：
10.1038/s42003-023-04611-w
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发表时间：
2023-03-01
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
chr19p13.1基因座内的等位基因与卵巢癌和乳腺癌的风险增加以及ANKLE1基因表达增加相关。ANKLE1的分子特征是作为一种内切核酸酶，有效地切割分支的DNA和细胞核和细胞质之间的穿梭。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表达仅限于成红细胞谱系，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。我们发现，ANKLE1在乳腺上皮细胞中的异位表达导致基因组不稳定和线粒体DNA（mtDNA）裂解。线粒体DNA降解导致线粒体自噬，并导致氧化磷酸化转变为糖酵解（瓦尔堡效应）。此外，mtDNA降解激活STAT1和上皮间质转化（EMT）基因的表达。线粒体含量的减少有助于细胞凋亡抗性，这可能允许癌前细胞避开细胞凋亡检查点并增殖。这些发现提供了证据表明，ANKLE1是chr19p13.1基因座中的致病癌症易感基因，并描述了ANKLE1高表达促进癌症风险的机制。锚蛋白重复序列和含LEM结构域的蛋白1（ANKLE1）在红细胞生成期间切割线粒体基因组，并且ANKLE1的异位表达促进基因组不稳定性和凋亡抗性，这有助于乳腺癌风险。
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. Ankyrin repeat and LEM-domain containing protein 1 (ANKLE1) cleaves the mitochondrial genome during erythropoiesis and ectopic expression of ANKLE1 promotes genome instability and apoptotic resistance, which contributes to breast cancer risk.
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影响因子：
3.7
作者：
Alves LR;Costa ES;Sorgine MH;Nascimento-Silva MC;Teodosio C;Bárcena P;Castro-Faria-Neto HC;Bozza PT;Orfao A;Oliveira PL;Maya-Monteiro CM
通讯作者：
Maya-Monteiro CM
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
4
作者：
Brachner A;Braun J;Ghodgaonkar M;Castor D;Zlopasa L;Ehrlich V;Jiricny J;Gotzmann J;Knasmüller S;Foisner R
通讯作者：
Foisner R
影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
3.9
作者：
Felipe Lima J;Nofech-Mozes S;Bayani J;Bartlett JM
通讯作者：
Bartlett JM