Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability
Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability
复制标题
自噬限制线粒体DNA损伤诱导的ENDOG（内切酶G）释放，以调节基因组的稳定性
DOI：
10.1080/15548627.2021.1874209
复制
发表时间：
2021-01-21
期刊：
影响因子：
13.3
通讯作者：
Chang, Zee-Fen
中科院分区：
文献类型：
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作者：
Chao, Tung;Shih, Hsueh-Tzu;Chang, Zee-Fen
遗传毒性损伤导致细胞核和线粒体DNA损伤，伴随巨自噬/自噬诱导。线粒体DNA（mtDNA）损伤在自噬对核DNA（nDNA）稳定性的要求中的作用尚不清楚。使用位点特异性DNA损伤的方法，我们表明，特定的nDNA损伤单独不需要自噬修复，除非在线粒体DNA损伤的存在。我们提供的证据表明，在IR照射诱导的mtDNA和nDNA损伤后，自噬抑制导致非凋亡线粒体通透性，线粒体ENDOG（内切核酸酶G）被释放并易位到细胞核中，以泰特（四甲基胞嘧啶双加氧酶）依赖的方式维持nDNA损伤。此外，阻断溶酶体功能足以增加线粒体DNA渗漏到胞质溶胶中的量，伴随着无ENDOG的线粒体斑点形成，同时伴有ENDOG核积聚。我们提出，自噬消除了由mtDNA损伤驱动的线粒体通透性所指定的线粒体，以防止ENDOG介导的基因组不稳定。最后，我们发现HBx，一种能够抑制自噬的B型肝炎病毒蛋白，也会导致线粒体通透性依赖性ENDOG在细胞核中的错误定位，并与B型肝炎病毒（HBV）介导的肝细胞癌的发展有关。
Genotoxic insult causes nuclear and mitochondrial DNA damages with macroautophagy/autophagy induction. The role of mitochondrial DNA (mtDNA) damage in the requirement of autophagy for nuclear DNA (nDNA) stability is unclear. Using site-specific DNA damage approaches, we show that specific nDNA damage alone does not require autophagy for repair unless in the presence of mtDNA damage. We provide evidence that after IR exposure-induced mtDNA and nDNA damages, autophagy suppression causes non-apoptotic mitochondrial permeability, by which mitochondrial ENDOG (endonuclease G) is released and translocated to nuclei to sustain nDNA damage in a TET (tet methylcytosine dioxygenase)-dependent manner. Furthermore, blocking lysosome function is sufficient to increase the amount of mtDNA leakage to the cytosol, accompanied by ENDOG-free mitochondrial puncta formation with concurrent ENDOG nuclear accumulation. We proposed that autophagy eliminates the mitochondria specified by mtDNA damage-driven mitochondrial permeability to prevent ENDOG-mediated genome instability. Finally, we showed that HBx, a hepatitis B viral protein capable of suppressing autophagy, also causes mitochondrial permeability-dependent ENDOG mis-localization in nuclei and is linked to hepatitis B virus (HBV)-mediated hepatocellular carcinoma development.