Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway.
Yeast telomere maintenance is globally controlled by programmed ribosomal frameshifting and the nonsense-mediated mRNA decay pathway.
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DOI：
10.4161/trla.24418
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发表时间：
2013-04-01
期刊：
影响因子：
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通讯作者：
Dinman JD
中科院分区：
文献类型：
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作者：
Advani VM;Belew AT;Dinman JD
我们先前已经表明，约10%的真核生物mRNA含有潜在的程序性-1核糖体移码（-1 PRF）信号，并且一些mRNA通过无义介导的mRNA衰变（NMD）途径通过将翻译核糖体引导到提前终止密码子来发挥mRNA不稳定元件的功能。在这里，探讨了-1PRF、NMD和端粒末端维护之间的联系。在编码酵母端粒酶的两种组分EST 1和EST 2的mRNA中，以及在编码参与将端粒酶募集到染色体末端的蛋白质STN 1和CDC 13的mRNA中，鉴定了功能性-1 PRF信号。所有这些元件都对先前已知的刺激或抑制-1 PRF的突变体和药物有反应，进一步支持它们通过典型机制促进-1 PRF的假设。所有这些因素都影响了报告基因mRNA的稳态丰度，并且这些因素促进了-1 PRF效率的广泛范围，从而能够确定-1 PRF效率和mRNA积累之间的反对数关系。内源性EST 1、EST 2、STN 1和CDC 13 mRNA的稳态丰度与突变体和药物促进的-1 PRF效率的变化类似地成反比，支持这些基因的表达在天然条件下由-1 PRF转录后控制的假设。EST 2的过表达通过消融-1 PRF信号或抑制NMD促进较短的端粒的形成和在G2/M边界的大出芽细胞的积累。提出了一个模型，描述了如何限制和维护正确的化学计量端粒酶组分的-1 PRF是用来维持酵母端粒长度。
We have previously shown that ~10% of all eukaryotic mRNAs contain potential programmed -1 ribosomal frameshifting (-1 PRF) signals and that some function as mRNA destabilizing elements through the Nonsense-Mediated mRNA Decay (NMD) pathway by directing translating ribosomes to premature termination codons. Here, the connection between -1 PRF, NMD and telomere end maintenance are explored. Functional -1 PRF signals were identified in the mRNAs encoding two components of yeast telomerase, EST1 and EST2, and in mRNAs encoding proteins involved in recruiting telomerase to chromosome ends, STN1 and CDC13. All of these elements responded to mutants and drugs previously known to stimulate or inhibit -1 PRF, further supporting the hypothesis that they promote -1 PRF through the canonical mechanism. All affected the steady-state abundance of a reporter mRNA and the wide range of -1 PRF efficiencies promoted by these elements enabled the determination of an inverse logarithmic relationship between -1 PRF efficiency and mRNA accumulation. Steady-state abundances of the endogenous EST1, EST2, STN1 and CDC13 mRNAs were similarly inversely proportional to changes in -1 PRF efficiency promoted by mutants and drugs, supporting the hypothesis that expression of these genes is post-transcriptionally controlled by -1 PRF under native conditions. Overexpression of EST2 by ablation of -1 PRF signals or inhibition of NMD promoted formation of shorter telomeres and accumulation of large budded cells at the G2/M boundary. A model is presented describing how limitation and maintenance of correct stoichiometries of telomerase components by -1 PRF is used to maintain yeast telomere length.