近期,，國際著名學(xué)術(shù)期刊PNAS（《美國科學(xué)院院報》）在線發(fā)表了中國科學(xué)技術(shù)大學(xué)生命科學(xué)學(xué)院施蘊渝教授與姚雪彪教授研究組的合作成果,。文章標(biāo)題為EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore -microtubule interactions in mitosis。該成果表明乙?；窹CAF對微管正端示蹤蛋白EB1的修飾可以精細(xì)調(diào)控細(xì)胞有絲分裂過程中染色體著絲粒（動點）與微管的連接,，該調(diào)控分子機(jī)制的闡明為癌癥的治療提供了一條新的線索。
細(xì)胞精確的自我復(fù)制是其生活史的重要組成部分,，復(fù)制的高保真性在生物及物種的繁衍生息過程中舉足輕重,。有絲分裂過程中染色體精確均等地分配到兩個子細(xì)胞中對于生命的延續(xù)與健康至關(guān)重要，若染色體的分配發(fā)生錯誤,，則會導(dǎo)致非整倍體和染色體不穩(wěn)定性的發(fā)生并且增加罹患癌癥的風(fēng)險,。有絲分裂的順利完成依賴于雙極紡錘體的形成、染色體沿紡錘體微管軌道精確移動、染色體通過著絲粒尋找并捕獲紡錘體微管正末端,，在這個連續(xù)的過程中,，微管正端示蹤蛋白具有至關(guān)重要的作用。微管末端結(jié)合蛋白1（End-binding protein 1, EB1)作為微管正端示蹤蛋白機(jī)器的核心分子,，定位于動點與微管連接處,，可以招募和調(diào)控其它微管正端示蹤蛋白在動點-微管連接處行使功能。
研究組綜合利用生物光子學(xué),、細(xì)胞生物學(xué)和結(jié)構(gòu)生物學(xué)技術(shù)手段,，揭示了著絲粒相關(guān)的乙酰化酶PCAF可以特異性地對EB1蛋白的220位賴氨酸進(jìn)行乙?；揎棧@個修飾影響了EB1蛋白中一個疏水窩狀結(jié)構(gòu)的穩(wěn)定性,，而這個疏水窩正是介導(dǎo)微管示蹤蛋白與EB1蛋白結(jié)合的關(guān)鍵部分,，因此該乙酰化修飾會影響整個微管示蹤蛋白機(jī)器的組裝,。實驗結(jié)果還發(fā)現(xiàn)EB1蛋白該位點的乙?；揎椝皆谟薪z分裂期增高，另外表達(dá)模擬乙?；腅B1蛋白的細(xì)胞中,，染色體排列在赤道板時會出現(xiàn)延遲，并持續(xù)激活有絲分裂中期檢驗點,。該項研究首次發(fā)現(xiàn)翻譯后修飾對于微管正端示蹤蛋白超復(fù)合物組裝的時空動力學(xué)調(diào)控機(jī)制及其在染色體穩(wěn)定性維系中的功能,。該調(diào)控機(jī)制的闡明對于進(jìn)一步理解有絲分裂的精密調(diào)控具有重要意義。（生物谷Bioon.com）
doi: 10.1073/pnas.1202639109
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EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis.
Xia P, Wang Z, Liu X, Wu B, Wang J, Ward T, Zhang L, Ding X, Gibbons G, Shi Y, Yao X.
In eukaryotes, microtubules are essential for cellular plasticity and dynamics. Here we show that P300/CBP-associated factor (PCAF), a kinetochore-associated acetyltransferase, acts as a negative modulator of microtubule stability through acetylation of EB1, a protein that controls the plus ends of microtubules. PCAF acetylates EB1 on K220 and disrupts the stability of a hydrophobic cavity on the dimerized EB1 C terminus, which was previously reported to interact with plus-end tracking proteins (TIPs) containing the SxIP motif. As determined with an EB1 acetyl-K220-specific antibody, K220 acetylation is dramatically increased in mitosis and localized to the spindle microtubule plus ends. Surprisingly, persistent acetylation of EB1 delays metaphase alignment, resulting in impaired checkpoint silencing. Consequently, suppression of Mad2 overrides mitotic arrest induced by persistent EB1 acetylation. Thus, our findings identify dynamic acetylation of EB1 as a molecular mechanism to orchestrate accurate kinetochore-microtubule interactions in mitosis. These results establish a previously uncharacterized regulatory mechanism governing localization of microtubule plus-end tracking proteins and thereby the plasticity and dynamics of cells.
