3月25日,来自美国堪萨斯大学医学中心的Peter Baumann等人在《自然》杂志在线发表了一篇关于端粒酶RNA生物发生的文章。这项研究明确了端粒酶生物发生的事件顺序,并阐明了Sm、Ls复合物以及甲基化酶Tgs1的作用。
端粒酶是一种逆转录酶,它可以使用其部分RNA作为模板来合成端粒重复单元。在大多数真核生物,染色体末端DNA的逐步丢失会被端粒酶所抑制。
许多癌细胞表达出高端粒酶活性,端粒酶亚基的突变与退行性综合症包括先天性角化不良和再生障碍性贫血有关。因此,改变端粒酶活性具有重要的治疗价值,这也提供了充足的动力来研究这种酶在人类细胞和模式系统中的生物合成及调节机制。
研究人员之前就鉴定了一个裂殖酵母端粒酶RNA亚基1(TER1)的前体,并证明成熟的3'末端于剪接体在一个单一的裂解反应中产生,这个反应类似于剪接的第一步。
部分重叠的剪接体的切割位点是一个推测的Sm蛋白的结合位点。Sm及Sm样(LSm)蛋白属于RNA结合蛋白中一个古老的家族。这个家族的所有成员在目标RNAs的特异位点形成了环状复合物,这在它们的生物合成、功能及翻转中有着极其重要的作用。
这篇文章里,研究人员阐明了典型的Sm环和Lsm2-8复合物顺序的结合在裂殖酵母TER1上。Sm环结合在TER1前体,刺激剪接体剪切,并通过Tgs1促进5'帽子的超甲基化。随后,Sm蛋白被Lsm2-8复合体取代,这促进了其与催化亚基的联系,保护了成熟的TER1 3'末端免受降解。(生物谷Deepblue编译)
doi: 10.1038/nature10924
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PMID:
Telomerase RNA biogenesis involves sequential binding by Sm and Lsm complexes
Wen Tang,Ram Kannan,Marco Blanchette & Peter Baumann.
In most eukaryotes, the progressive loss of chromosome-terminal DNA sequences is counteracted by the enzyme telomerase, a reverse transcriptase that uses part of an RNA subunit as template to synthesize telomeric repeats.Many cancer cells express high telomerase activity, and mutations in telomerase subunits are associated with degenerative syndromes including dyskeratosis congenita and aplastic anaemia.The therapeutic value of altering telomerase activity thus provides ample impetus to study the biogenesis and regulation of this enzyme in human cells and model systems.We have previously identified a precursor of the fission yeast telomerase RNA subunit (TER1) and demonstrated that the mature 3′-end is generated by the spliceosome in a single cleavage reaction akin to the first step of splicing.Directly upstream and partly overlapping with the spliceosomal cleavage site is a putative binding site for Sm proteins. Sm and like-Sm (LSm) proteins belong to an ancient family of RNA-binding proteins represented in all three domains of life. Members of this family form ring complexes on specific sets of target RNAs and have critical roles in their biogenesis, function and turnover.Here we demonstrate that the canonical Sm ring and the Lsm2–8 complex sequentially associate with fission yeast TER1. The Sm ring binds to the TER1 precursor,stimulates spliceosomal cleavage and promotes the hypermethylation of the 5′-cap by Tgs1. Sm proteins are then replaced by the Lsm2–8 complex, which promotes the association with the catalytic subunit and protects the mature 3′-end of TER1 from exonucleolytic degradation.Our findings define the sequence of events that occur during telomerase biogenesis and characterize roles for Sm and Lsm complexes as well as for the methylase Tgs1.