The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4
The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4
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DOI：
10.1016/j.dnarep.2004.06.017
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发表时间：
2004-11-02
期刊：
影响因子：
3.8
通讯作者：
Caldecott, KW
中科院分区：
文献类型：
--
作者：
Clements, PM;Breslin, C;Caldecott, KW
共济失调-动眼肌失用症1 （AOA1）是一种常染色体隐性神经退行性疾病，与共济失调-毛细血管扩张症（A-T）相似。AOA1是由编码aprataxin的基因突变引起的，aprataxin是一种生理功能目前尚不清楚的蛋白质。我们在这里报道，与a - t相反，AOA1细胞系既没有表现出抗辐射DNA合成，也没有在DNA损伤后磷酸化ATM下游靶点的能力降低，这表明AOA1缺乏a - t特有的细胞周期检查点缺陷。此外，AOA1原代成纤维细胞对电离辐射、过氧化氢和甲磺酸甲酯（MMS）仅表现出轻度敏感性。然而，引人注目的是，在体外和体内，aprataxin与DNA链断裂修复蛋白XRCC1和XRCC4发生物理相互作用。Aprataxin具有一个分叉叉头相关（FHA）结构域，与多核苷酸激酶中的FHA结构域非常相似，并且似乎通过该结构域介导ck2磷酸化的XRCC1和XRCC4的相互作用。因此，Aprataxin在物理上与DNA单链和双链断裂修复机制相关，这提高了AOA1是一种新型DNA损伤反应缺陷性疾病的可能性。(C) 2004 Elsevier B.V.版权所有
Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease. (C) 2004 Elsevier B.V. All rights reserved.