Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity
Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity
复制标题
DOI：
10.1038/nature12824
复制
发表时间：
2014-02-06
期刊：
影响因子：
64.8
通讯作者：
Williams, R. Scott
中科院分区：
文献类型：
--
作者：
Tumbale, Percy;Williams, Jessica S.;Williams, R. Scott
通过ATP依赖性DNA连接酶使用的三步DNA连接反应确保真核基因组的忠实维持和繁殖（1，2）。奇怪的是，当DNA连接酶遇到具有异常DNA末端的切口DNA结构时，DNA连接酶催化活性可通过产生化学加合的毒性5 '-腺苷酸化（5'-AMP）DNA损伤的失败连接产生和/或加剧DNA损伤（3-6）。Aprataxin（APTX）逆转DNA腺苷酸化，但腺苷酸化修复的背景尚不清楚。在这里，我们研究的重要性APTX RNase-H2依赖切除修复（RER）的病变，是非常频繁地引入到DNA，核糖核苷酸。我们表明，连接酶产生腺苷酸化的5'端含有核糖核酸酶H2切口的特征。APTX有效地修复腺苷酸化的RNA-DNA，并在RNA-DNA损伤反应（RDDR）中起作用，促进细胞存活并防止经历RER的芽殖酵母中的S期检查点激活。人APTX-RNA-DNA-AMP-Zn复合物的结构-功能研究确定了检测和逆转RNA-DNA连接处腺苷酸化的机制。这涉及A型RNA结合、适当的蛋白质折叠和构象变化，所有这些都受到共济失调伴眼用不能1的遗传性APTX突变的影响。总之，这些结果表明腺苷酸化RNA-DNA的积累可能有助于神经系统疾病。
Faithful maintenance and propagation of eukaryotic genomes is ensured by three-step DNA ligation reactions used by ATP-dependent DNA ligases(1,2). Paradoxically, when DNA ligases encounter nicked DNA structures with abnormal DNA termini, DNA ligase catalytic activity can generate and/or exacerbate DNA damage through abortive ligation that produces chemically adducted, toxic 5'-adenylated (5'-AMP) DNA lesions(3-6). Aprataxin (APTX) reverses DNA adenylation but the context for deadenylation repair is unclear. Here we examine the importance of APTX to RNase-H2-dependent excision repair (RER) of a lesion that is very frequently introduced into DNA, a ribonucleotide. We show that ligases generate adenylated 5' ends containing a ribose characteristic of RNase H2 incision. APTX efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response (RDDR), promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RER. Structure-function studies of human APTX-RNA-DNA-AMP-Zn complexes define a mechanism for detecting and reversing adenylation at RNA-DNA junctions. This involves A-form RNA binding, proper protein folding and conformational changes, all of which are affected by heritable APTX mutations in ataxia with oculomotor apraxia 1. Together, these results indicate that accumulation of adenylated RNA-DNA may contribute to neurological disease.