Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome.
Arsenite toxicity is regulated by queuine availability and oxidation-induced reprogramming of the human tRNA epitranscriptome.
复制标题
DOI：
10.1073/pnas.2123529119
复制
发表时间：
2022-09-20
影响因子：
11.1
通讯作者：
Begley, Thomas J.
中科院分区：
文献类型：
--
作者：
Huber, Sabrina M.;Begley, Ulrike;Sarkar, Anwesha;Gasperi, William;Davis, Evan T.;Surampudi, Vasudha;Lee, May;Melendez, J. Andres;Dedon, Peter C.;Begley, Thomas J.
砷是一种有几个世纪历史的天然有毒物质，其对细胞的影响仍然知之甚少。这项工作的意义有三方面。首先，在一系列氧化和烷基化剂中，亚砷酸盐暴露导致转运RNA （tRNA）表转录组中不稳定队列的独特重编程，这依赖于微量营养素前体队列，并与已知与亚砷酸盐毒性相关的代谢蛋白翻译中的密码子偏向移位有关。其次，我们发现tRNA表转录组受到暴露于各种毒物的动态和差异调节。最后，研究结果表明，作为一种微量营养素，钙的作用决定了人体细胞对有毒压力的反应。细胞在转录和翻译两个层面上通过调控基因表达来应对环境应激。人类表转录组的约50个修饰的核糖核苷酸有助于后者，越来越多的证据表明，转移RNA （tRNA）摆动修饰的动态调节导致来自密码子偏向基因的应激反应蛋白的选择性翻译。在这里，我们发现人类肝癌细胞对亚砷酸盐暴露的反应是由queuine的可用性调节的，queuine是一种微量营养素，是读取GUN密码子的tRNAs上的振荡修饰queuosine (Q)的必要前体。在氧化剂和烷基化剂等氧浓度下，亚砷酸盐暴露导致Q的氧化特异性增加，这与参与能量代谢的密码子偏倚基因的蛋白上调有关。限制排队增加亚砷酸盐诱导的细胞死亡，改变翻译，增加活性氧水平，并引起线粒体功能障碍。除了展示亚砷酸盐毒性和反应的表转录组学方面外，我们的研究结果还强调了环境暴露、应激耐受性、RNA修饰和微量营养素之间的联系。
Arsenic is a centuries-old, naturally occurring toxicant, and its cellular effect is still poorly understood. The significance of this work is three-fold. First, among a battery of oxidizing and alkylating agents, arsenite exposure caused a unique reprogramming of wobble queuosine in the transfer RNA (tRNA) epitranscriptome, which depended upon the micronutrient precursor queuine and was linked to codon-biased shifts in the translation of metabolic proteins known to be linked to arsenite toxicity. Second, we showed that the tRNA epitranscriptome is dynamically and differentially regulated by exposure to a variety of toxicants. Finally, the results have implications for the role of queuine as a micronutrient that determines the human cell response to toxic stresses. Cells respond to environmental stress by regulating gene expression at the level of both transcription and translation. The ∼50 modified ribonucleotides of the human epitranscriptome contribute to the latter, with mounting evidence that dynamic regulation of transfer RNA (tRNA) wobble modifications leads to selective translation of stress response proteins from codon-biased genes. Here we show that the response of human hepatocellular carcinoma cells to arsenite exposure is regulated by the availability of queuine, a micronutrient and essential precursor to the wobble modification queuosine (Q) on tRNAs reading GUN codons. Among oxidizing and alkylating agents at equitoxic concentrations, arsenite exposure caused an oxidant-specific increase in Q that correlated with up-regulation of proteins from codon-biased genes involved in energy metabolism. Limiting queuine increased arsenite-induced cell death, altered translation, increased reactive oxygen species levels, and caused mitochondrial dysfunction. In addition to demonstrating an epitranscriptomic facet of arsenite toxicity and response, our results highlight the links between environmental exposures, stress tolerance, RNA modifications, and micronutrients.
登录
查看更多内容
影响因子：
16
作者：
Begley, Ulrike;Dyavaiah, Madhu;Begley, Thomas J.
通讯作者：
Begley, Thomas J.
影响因子：
14.9
作者：
Kimura S;Miyauchi K;Ikeuchi Y;Thiaville PC;Crécy-Lagard Vd;Suzuki T
通讯作者：
Suzuki T
影响因子：
3.7
作者：
Endres L;Begley U;Clark R;Gu C;Dziergowska A;Małkiewicz A;Melendez JA;Dedon PC;Begley TJ
通讯作者：
Begley TJ
影响因子：
4.6
作者：
Kulkarni O;Sugier PE;Guibon J;Boland-Augé A;Lonjou C;Bacq-Daian D;Olaso R;Rubino C;Souchard V;Rachedi F;Lence-Anta JJ;Ortiz RM;Xhaard C;Laurent-Puig P;Mulot C;Guizard AV;Schvartz C;Boutron-Ruault MC;Ostroumova E;Kesminiene A;Deleuze JF;Guénel P;De Vathaire F;Truong T;Lesueur F
通讯作者：
Lesueur F
影响因子：
14.8
作者：
Kimura S;Dedon PC;Waldor MK
通讯作者：
Waldor MK