Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3′-phosphate and 3′-phosphoglycolate ends
Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3′-phosphate and 3′-phosphoglycolate ends
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DOI：
10.1093/nar/gkm158
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发表时间：
2007-06-01
影响因子：
14.9
通讯作者：
Onodera, Osamu
中科院分区：
文献类型：
--
作者：
Takahashi, Tetsuya;Tada, Masayoshi;Onodera, Osamu
Aprataxin是早发性共济失调伴眼球运动性失用和低蛋白血症/共济失调伴动眼运动性失用1型(EAOH/AOA1)的致病基因产物，其临床症状以神经系统为主。虽然aprataxin已被认为与DNA单链断裂修复(SSBR)有关，但aprataxin的生理功能仍有待阐明。DNA单链断裂(DNA Single-strand Break，SSB)是由内源性活性氧或外源性遗传毒性物质持续产生的，通常具有受损的3‘-末端，包括3’-磷酸、3‘-磷酸乙醇酸或3’-α、β-不饱和醛末端。这些受损的3‘-端应恢复为3’-羟基末端，以供后续修复过程使用。在这里，我们通过体外实验证明，重组人aprataxin特异性地去除DNA 3‘端的3’-磷酸乙醇酸和3‘-磷酸末端，而不是3’-α，β-不饱和醛末端，并且可以与DNA聚合酶β和DNA连接酶III一起作用于这些受损的3‘端修复SSB。此外，与疾病相关的APRATAIN突变形式缺乏这种去除活性。结果表明，APRATAXIN在SSBR中起重要作用，即它清除3‘端的阻断分子，而3’端损伤的未修复SSB的积累是EAOH/AOA1发病的基础。这些发现将为神经元退化和DNA修复的潜在机制提供新的见解。
Aprataxin is the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ ataxia with oculomotor apraxia type 1 (EAOH/AOA1), the clinical symptoms of which are predominantly neurological. Although aprataxin has been suggested to be related to DNA single-strand break repair (SSBR), the physiological function of aprataxin remains to be elucidated. DNA single-strand breaks (SSBs) continually produced by endogenous reactive oxygen species or exogenous genotoxic agents, typically possess damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-alpha, beta-unsaturated aldehyde ends. These damaged 3'-ends should be restored to 3'-hydroxyl ends for subsequent repair processes. Here we demonstrate by in vitro assay that recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-alpha, beta-unsaturated aldehyde ends, and can act with DNA polymerase beta and DNA ligase III to repair SSBs with these damaged 3'-ends. Furthermore, disease-associated mutant forms of aprataxin lack this removal activity. The findings indicate that aprataxin has an important role in SSBR, that is, it removes blocking molecules from 3'-ends, and that the accumulation of unrepaired SSBs with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons.