Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase
Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase
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DOI：
10.1172/jci200420926
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发表时间：
2004-06-01
影响因子：
15.9
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
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作者：
Endres, M;Biniszkiewicz, D;Jaenisch, R
尿嘧啶-DNA糖基酶(UNG)参与核内和线粒体DNA中尿嘧啶残基的碱基切除修复。通过基因打靶产生的Ung基因敲除小鼠是可存活的、可生育的、表型正常的，并具有规则的突变率。然而，当暴露于一氧化氮供体时，Ung(-/-)成纤维细胞基因组中的尿嘧啶/胞嘧啶比率增加，细胞死亡加剧。在联合缺氧-葡萄糖剥夺后，Ung(-/-)原代皮质神经元对细胞死亡的易感性增加，这与早期线粒体功能障碍有关。在体内，Ling在幼龄WT小鼠脑组织中的表达和活性较低，但在可逆性大脑中动脉闭塞和再灌流后显著增加。此外，与产仔对照小鼠相比，Ung(-/-)小鼠的脑梗塞面积显著增加。总之，我们的结果提供了令人信服的证据，证明LING在脑缺血后的组织修复中起着重要的作用。
Uracil-DNA glycosylase (UNG) is involved in base excision repair of aberrant uracil residues in nuclear and mitochondrial DNA. Ung knockout mice generated by gene targeting are viable, fertile, and phenotypically normal and have regular mutation rates. However, when exposed to a nitric oxide donor, Ung(-/-) fibroblasts show an increase in the uracil/cytosine ratio in the genome and augmented cell death. After combined oxygen-glucose deprivation, Ung(-/-) primary cortical neurons have increased vulnerability to cell death, which is associated with early mitochondrial dysfunction. In vivo, LING expression and activity are low in brains of naive WT mice but increase significantly after reversible middle cerebral artery occlusion and reperfusion. Moreover, major increases in infarct size are observed in Ung(-/-) mice compared with littermate control mice. In conclusion, our results provide compelling evidence that LING is of major importance for tissue repair after brain ischemia.