3月25日,，來(lái)自美國(guó)堪薩斯大學(xué)醫(yī)學(xué)中心的Peter Baumann等人在《自然》雜志在線發(fā)表了一篇關(guān)于端粒酶RNA生物發(fā)生的文章。這項(xiàng)研究明確了端粒酶生物發(fā)生的事件順序,，并闡明了Sm,、Ls復(fù)合物以及甲基化酶Tgs1的作用。
端粒酶是一種逆轉(zhuǎn)錄酶,，它可以使用其部分RNA作為模板來(lái)合成端粒重復(fù)單元,。在大多數(shù)真核生物，染色體末端DNA的逐步丟失會(huì)被端粒酶所抑制,。
許多癌細(xì)胞表達(dá)出高端粒酶活性,，端粒酶亞基的突變與退行性綜合癥包括先天性角化不良和再生障礙性貧血有關(guān)。因此,，改變端粒酶活性具有重要的治療價(jià)值,，這也提供了充足的動(dòng)力來(lái)研究這種酶在人類細(xì)胞和模式系統(tǒng)中的生物合成及調(diào)節(jié)機(jī)制。
研究人員之前就鑒定了一個(gè)裂殖酵母端粒酶RNA亞基1(TER1)的前體,，并證明成熟的3'末端于剪接體在一個(gè)單一的裂解反應(yīng)中產(chǎn)生,，這個(gè)反應(yīng)類似于剪接的第一步。
部分重疊的剪接體的切割位點(diǎn)是一個(gè)推測(cè)的Sm蛋白的結(jié)合位點(diǎn),。Sm及Sm樣(LSm)蛋白屬于RNA結(jié)合蛋白中一個(gè)古老的家族。這個(gè)家族的所有成員在目標(biāo)RNAs的特異位點(diǎn)形成了環(huán)狀復(fù)合物,，這在它們的生物合成,、功能及翻轉(zhuǎn)中有著極其重要的作用。
這篇文章里,，研究人員闡明了典型的Sm環(huán)和Lsm2-8復(fù)合物順序的結(jié)合在裂殖酵母TER1上,。Sm環(huán)結(jié)合在TER1前體，刺激剪接體剪切,，并通過(guò)Tgs1促進(jìn)5'帽子的超甲基化,。隨后，Sm蛋白被Lsm2-8復(fù)合體取代,，這促進(jìn)了其與催化亞基的聯(lián)系,，保護(hù)了成熟的TER1 3'末端免受降解。（生物谷Deepblue編譯）
doi: 10.1038/nature10924
PMC:
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.
