A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans.
A Role for the Nonsense-Mediated mRNA Decay Pathway in Maintaining Genome Stability in Caenorhabditis elegans.
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DOI：
10.1534/genetics.117.203414
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发表时间：
2017-08
期刊：
影响因子：
3.3
通讯作者：
Gartner A
中科院分区：
文献类型：
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作者：
González-Huici V;Wang B;Gartner A
电离辐射（IR）通常用于癌症治疗，是DNA双链断裂（DSB）的主要来源，DSB是DNA损伤的最毒性形式之一。我们已经使用秀丽隐杆线虫作为无脊椎动物模型来鉴定修复IR造成的DNA损伤所需的新因子。我们已经进行了无偏倚的遗传筛选，发现SMG-1突变赋予对IR的强烈超敏性。SMG-1是一种参与介导无义介导的mRNA衰变（NMD）的磷酸肌醇-3激酶（PI 3 K）含有提前终止密码子的转录物，与处于DNA损伤信号通路顶端的ATM和ATR激酶相关。当其他介导NMD的基因突变时，也会发生对IR的超敏反应。对博来霉素（一种已知诱导DSB的药物）的超敏感性进一步支持NMD途径突变体在DSB修复中有缺陷。用烷化剂或UV照射处理后未观察到超敏反应。我们发现SMG-1主要作用于有丝分裂的生殖细胞，并在胚胎和幼虫发育后期。基于上位性实验，SMG-1似乎不作用于已知修复DNA DSB的三种主要途径中的任何一种，即同源重组（HR）、非同源末端连接（NHEJ）和微同源介导的末端连接（MMEJ）。我们推测，SMG-1激酶活性可以在DNA损伤后被激活以磷酸化特异性DNA修复蛋白和/或NMD失活可能导致异常mRNA，从而导致合成故障DNA修复蛋白。
Ionizing radiation (IR) is commonly used in cancer therapy and is a main source of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA damage. We have used Caenorhabditis elegans as an invertebrate model to identify novel factors required for repair of DNA damage inflicted by IR. We have performed an unbiased genetic screen, finding that smg-1 mutations confer strong hyper-sensitivity to IR. SMG-1 is a phosphoinositide-3 kinase (PI3K) involved in mediating nonsense-mediated mRNA decay (NMD) of transcripts containing premature stop codons and related to the ATM and ATR kinases which are at the apex of DNA damage signaling pathways. Hyper-sensitivity to IR also occurs when other genes mediating NMD are mutated. The hyper-sensitivity to bleomycin, a drug known to induce DSBs, further supports that NMD pathway mutants are defective in DSB repair. Hyper-sensitivity was not observed upon treatment with alkylating agents or UV irradiation. We show that SMG-1 mainly acts in mitotically dividing germ cells, and during late embryonic and larval development. Based on epistasis experiments, SMG-1 does not appear to act in any of the three major pathways known to mend DNA DSBs, namely homologous recombination (HR), nonhomologous end-joining (NHEJ), and microhomology-mediated end-joining (MMEJ). We speculate that SMG-1 kinase activity could be activated following DNA damage to phosphorylate specific DNA repair proteins and/or that NMD inactivation may lead to aberrant mRNAs leading to synthesis of malfunctioning DNA repair proteins.