2012年11月23日 訊 /生物谷BIOON/ --染色體是一種較長(zhǎng)的線性DNA分子,，其可以在末端形成特殊的DNA結(jié)構(gòu)，名為端粒,，其對(duì)于DNA分子具有保護(hù)作用,。端粒可以通過與端粒酶以及一些附屬蛋白質(zhì)進(jìn)行作用來維持其功能及DNA分子的穩(wěn)定性,。來自美國(guó)賓夕法尼亞大學(xué)威斯達(dá)研究所的研究者揭示了酵母中這些關(guān)鍵蛋白質(zhì)的重要結(jié)構(gòu),。相關(guān)研究結(jié)果于近日刊登在國(guó)際雜志Structure上。
在老化細(xì)胞中,，DNA的端粒最終會(huì)比端粒酶更快損害掉,，而其輔助蛋白質(zhì)可以維持其不斷退化消失的情況，在癌癥中,，腫瘤細(xì)胞可以劫持這個(gè)過程,，使得細(xì)胞不斷增殖生長(zhǎng)。Cdc13是一種輔助蛋白質(zhì),，其對(duì)于酵母細(xì)胞端粒的維持是不可缺少的,，對(duì)于酵母細(xì)胞的活力也是很重要的。
本項(xiàng)研究中,，研究者揭示了Cdc13特殊區(qū)域的突變?nèi)绾我l(fā)端粒的缺陷最終危害DNA,。研究者發(fā)現(xiàn)Cdc13的突變區(qū)域-OB2，可以抑制Cdc13拷貝之間互相結(jié)合,，這就幫助解釋了關(guān)鍵的端粒維持蛋白質(zhì)的生物學(xué)功能,，或許為開發(fā)抗癌療法提供思路。
Cdc13在端粒的復(fù)制過程中扮演著雙重的作用,，第一,，其可以幫助細(xì)胞中天然的DNA分子的修復(fù)機(jī)制不受破碎DNA的影響；第二,，Cdc13可以補(bǔ)充端粒酶及相關(guān)蛋白質(zhì)來增強(qiáng)端粒的功能,。在酵母細(xì)胞中，端?？梢员欢喾N蛋白質(zhì)復(fù)合物所修飾,，俗稱為CST，包括蛋白質(zhì)Cdc13（C）,、Stn1（S）以及Ten（t）,，Cdc13是多蛋白復(fù)合物的重要成員，其可以為端粒帶上“帽子”并且補(bǔ)充關(guān)鍵酶的量,。
研究者最終表示,，OB2的二聚化作用是端粒CST復(fù)合物裝配所必須的，當(dāng)破壞了這種結(jié)構(gòu)域的二聚化作用,，就會(huì)破壞這種CST復(fù)合物的作用,，從而就會(huì)調(diào)節(jié)端粒的長(zhǎng)度。（生物谷Bioon.com）
編譯自：Aging: Scientists Further Unravel Telomere Biology
doi:10.1016/j.str.2012.10.012
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PMID:
Cdc13 OB2 Dimerization Required for Productive Stn1 Binding and Efficient Telomere Maintenance
Mark Mason, Jennifer J. Wanat, Sandy Harper, David C. Schultz, David W. Speicher, F. Brad Johnson, Emmanuel Skordalakes
Cdc13 is an essential yeast protein required for telomere length regulation and genome stability. It does so via its telomere-capping properties and by regulating telomerase access to the telomeres. The crystal structure of the Saccharomyces cerevisiae Cdc13 domain located between the recruitment and DNA binding domains reveals an oligonucleotide-oligosaccharide binding fold (OB2) with unusually long loops extending from the core of the protein. These loops are involved in extensive interactions between two Cdc13 OB2 folds leading to stable homodimerization. Interestingly, the functionally impaired cdc13-1 mutation inhibits OB2 dimerization. Biochemical assays indicate OB2 is not involved in telomeric DNA or Stn1 binding. However, disruption of the OB2 dimer in full-length Cdc13 affects Cdc13-Stn1 association, leading to telomere length deregulation, increased temperature sensitivity, and Stn1 binding defects. We therefore propose that dimerization of the OB2 domain of Cdc13 is required for proper Cdc13, Stn1, Ten1 (CST) assembly and productive telomere capping.
