Interplay between nonsense-mediated mRNA decay and DNA damage response pathways reveals that Stn1 and Ten1 are the key CST telomere-cap components.
Interplay between nonsense-mediated mRNA decay and DNA damage response pathways reveals that Stn1 and Ten1 are the key CST telomere-cap components.
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DOI：
10.1016/j.celrep.2014.04.017
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发表时间：
2014-05-22
期刊：
影响因子：
8.8
通讯作者：
Lydall D
中科院分区：
文献类型：
--
作者：
Holstein EM;Clark KR;Lydall D
在哺乳动物和酵母中，大量不同的蛋白质，包括CST复合物、无义介导的衰变（NMD）和DNA损伤反应（DDR）蛋白，在端粒处起重要作用。在这里，我们报告说，NMD，像DDR，影响单链DNA（ssDNA）的生产在未加帽的端粒。值得注意的是，我们发现，当DDR和NMD途径被灭活时，对CST的组成部分之一Cdc 13的需求可以被有效地绕过。然而，相同的遗传干预并不能绕过对Cdc 13的伙伴Stn 1和Ten 1的需要。我们发现，禁用NMD改变了端粒的CST组分的化学计量，并允许Stn 1在没有Cdc 13的情况下结合端粒。我们的数据支持的模型，Stn 1和Ten 1可以在Cdc 13独立的方式发挥作用，并有跨真核生物的CST组件的功能的影响。STN 1和TEN 1在芽殖酵母中比CDC 13发挥更重要的作用有几条途径绕过cdc 13 Δ，但不是stn 1 Δ或ten 1 Δ CST的组分以不同的比例结合端粒NMD途径影响ssDNA在未加帽的端粒上的积累芽殖酵母CST复合物保护端粒末端免受DNA损伤反应（DDR）的降解。所有三个CST亚基在酵母和哺乳动物之间是保守的，并且通常对于酵母细胞活力是必需的。Holstein等发表在在这里显示，当DDR和无义介导的mRNA衰减的方面被禁用时，细胞在没有Cdc 13的情况下无限期地存活，但没有Stn 1或Ten 1。Stn 1在没有Cdc 13的情况下仍然被募集到端粒中;因此，Stn 1和Ten 1可以独立于Cdc 13而覆盖端粒。
A large and diverse set of proteins, including CST complex, nonsense mediated decay (NMD), and DNA damage response (DDR) proteins, play important roles at the telomere in mammals and yeast. Here, we report that NMD, like the DDR, affects single-stranded DNA (ssDNA) production at uncapped telomeres. Remarkably, we find that the requirement for Cdc13, one of the components of CST, can be efficiently bypassed when aspects of DDR and NMD pathways are inactivated. However, identical genetic interventions do not bypass the need for Stn1 and Ten1, the partners of Cdc13. We show that disabling NMD alters the stoichiometry of CST components at telomeres and permits Stn1 to bind telomeres in the absence of Cdc13. Our data support a model that Stn1 and Ten1 can function in a Cdc13-independent manner and have implications for the function of CST components across eukaryotes. STN1 and TEN1 play more critical roles in budding yeast than CDC13 Several routes bypass cdc13Δ, but not stn1Δ or ten1Δ Components of CST bind telomeres with different ratios NMD pathways affect accumulation of ssDNA at uncapped telomeres The budding yeast CST complex protects telomere ends from degradation by the DNA damage response (DDR). All three CST subunits are conserved between yeast and mammals and are normally essential for yeast cell viability. Holstein et al. show here that when aspects of the DDR and nonsense-mediated mRNA decay are disabled, cells survive indefinitely without Cdc13 but not Stn1 or Ten1. Stn1 is still recruited to telomeres without Cdc13; thus, Stn1 and Ten1 may cap the telomere independently of Cdc13.