Gradual processing of the ITS1 from the nucleolus to the cytoplasm during synthesis of the human 18S rRNA.
Gradual processing of the ITS1 from the nucleolus to the cytoplasm during synthesis of the human 18S rRNA.
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DOI：
10.1093/nar/gkt160
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发表时间：
2013-04
影响因子：
14.9
通讯作者：
Gleizes PE
中科院分区：
文献类型：
--
作者：
Preti M;O'Donohue MF;Montel-Lehry N;Bortolin-Cavaillé ML;Choesmel V;Gleizes PE
核糖体生物合成的缺陷触发应激反应途径，其干扰几种遗传疾病中的细胞增殖和分化。在Diamond-Blackfan贫血（DBA）中，一种先天性成红细胞减少症，核糖体蛋白基因的突变经常干扰内部转录间隔区1（ITS 1）的加工，其机制在人类细胞中仍然难以捉摸。使用功能丧失实验和广泛的RNA分析，我们已经确定了ITS 1中内切核酸酶切E的精确位置，ITS 1产生18 S-E中间体，18 S rRNA的最后前体。出乎意料的是，这种切割之后，在前40 S颗粒的核输出期间，18 S-E前体的3′-5′核酸外切酶切修剪，这为18 S rRNA的形成设定了一种新的机制，与酵母中建立的机制明显不同。此外，在位点E处的切割之后还通过核酸外切酶XRN 2对ITS 1进行5′-3′核酸外切酶切。干扰这一步敲低大亚基核糖体蛋白RPL 26，这是最近与DBA，揭示了一个高度保守的顺式作用序列在ITS 1加工的推定作用。这些数据为人类细胞中ITS 1消除的原始机制提供了新的视角，并为进一步研究DBA连接的核糖体蛋白在这一过程中的相互作用提供了机制框架。
Defects in ribosome biogenesis trigger stress response pathways, which perturb cell proliferation and differentiation in several genetic diseases. In Diamond–Blackfan anemia (DBA), a congenital erythroblastopenia, mutations in ribosomal protein genes often interfere with the processing of the internal transcribed spacer 1 (ITS1), the mechanism of which remains elusive in human cells. Using loss-of-function experiments and extensive RNA analysis, we have defined the precise position of the endonucleolytic cleavage E in the ITS1, which generates the 18S-E intermediate, the last precursor to the 18S rRNA. Unexpectedly, this cleavage is followed by 3′–5′ exonucleolytic trimming of the 18S-E precursor during nuclear export of the pre-40S particle, which sets a new mechanism for 18S rRNA formation clearly different from that established in yeast. In addition, cleavage at site E is also followed by 5′–3′ exonucleolytic trimming of the ITS1 by exonuclease XRN2. Perturbation of this step on knockdown of the large subunit ribosomal protein RPL26, which was recently associated to DBA, reveals the putative role of a highly conserved cis-acting sequence in ITS1 processing. These data cast new light on the original mechanism of ITS1 elimination in human cells and provide a mechanistic framework to further study the interplay of DBA-linked ribosomal proteins in this process.
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影响因子：
3.9
作者：
Boria, Ilenia;Garelli, Emanuela;Gazda, Hanna T.;Aspesi, Anna;Quarello, Paola;Pavesi, Elisa;Ferrante, Daniela;Meerpohl, Joerg J.;Kartal, Mutlu;Da Costa, Lydie;Proust, Alexis;Leblanc, Thierry;Simansour, Maud;Dahl, Niklas;Froejmark, Anne-Sophie;Pospisilova, Dagmar;Cmejla, Radek;Beggs, Alan H.;Sheen, Mee R.;Landowski, Michael;Buros, Christopher M.;Clinton, Catherine M.;Dobson, Lori J.;Vlachos, Adrianna;Atsidaftos, Eva;Lipton, Jeffrey M.;Ellis, Steven R.;Ramenghi, Ugo;Dianzani, Irma
通讯作者：
Dianzani, Irma
影响因子：
20.3
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
20.3
作者：
Flygare, Johan;Aspesi, Anna;Ellis, Steven R.
通讯作者：
Ellis, Steven R.
影响因子：
2.3
作者：
Idol, Rachel A.;Robledo, Sara;Mason, Philip J.
通讯作者：
Mason, Philip J.
影响因子：
16.8
作者：
Dziembowski, Andrzej;Lorentzen, Esben;Seraphin, Bertrand
通讯作者：
Seraphin, Bertrand