Oxidized base damage and single-strand break repair in mammalian genomes: role of disordered regions and posttranslational modifications in early enzymes.
Oxidized base damage and single-strand break repair in mammalian genomes: role of disordered regions and posttranslational modifications in early enzymes.
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DOI：
10.1016/b978-0-12-387665-2.00006-7
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发表时间：
2012
影响因子：
--
通讯作者：
Mitra, Sankar
中科院分区：
文献类型：
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作者：
Hegde, Muralidhar L.;Izumi, Tadahide;Mitra, Sankar
由活性氧引起的氧化性基因组损伤包括氧化碱基、脱碱基（AP）位点和单链断裂，所有这些都通过进化上保守的碱基切除修复/单链断裂修复（BER/SSBR）途径修复。哺乳动物细胞中的BER/SSBR是复杂的，具有优选和备用子途径，并且与基因组复制和转录相关。早期BER/SSBR酶，即DNA糖基化酶（DG）和末端加工蛋白，如无碱基核酸内切酶1（APE 1），通过成对相互作用与下游修复（和其他非经典）蛋白形成复合物。此外，哺乳动物早期BER/ SSBR酶的一个独特特征是存在其大肠杆菌原型中不存在的无序末端延伸。这些非保守片段通常包含细胞器靶向信号，共同的相互作用界面，以及可能参与调节其修复功能（包括病变扫描）的翻译后修饰位点。最后，BER/SSBR缺陷与癌症，衰老和人类神经退行性疾病的联系，以及BER/SSBR的治疗靶向进行了讨论。
Oxidative genome damage induced by reactive oxygen species includes oxidized bases, abasic (AP) sites, and single-strand breaks, all of which are repaired via the evolutionarily conserved base excision repair/single-strand break repair (BER/SSBR) pathway. BER/SSBR in mammalian cells is complex, with preferred and backup sub-pathways, and is linked to genome replication and transcription. The early BER/SSBR enzymes, namely, DNA glycosylases (DGs) and the end-processing proteins such as abasic endonuclease 1 (APE1), form complexes with downstream repair (and other noncanonical) proteins via pairwise interactions. Furthermore, a unique feature of mammalian early BER/ SSBR enzymes is the presence of a disordered terminal extension that is absent in their Escherichia coli prototypes. These nonconserved segments usually contain organelle-targeting signals, common interaction interfaces, and sites of posttranslational modifications that may be involved in regulating their repair function including lesion scanning. Finally, the linkage of BER/SSBR deficiency to cancer, aging, and human neurodegenerative diseases, and therapeutic targeting of BER/SSBR are discussed.