來(lái)自阿拉巴馬州大學(xué)生物化學(xué)與分子遺傳學(xué)系，細(xì)胞生物學(xué)系,，紀(jì)念斯隆－凱特琳癌癥中心（Memorial Sloan -Kettering Cancer Center）的研究人員識(shí)別出了組蛋白H2A的主要去泛素化（deubiquitination）過(guò)程，也證明H2A去泛素化是細(xì)胞周期和基因表達(dá)的關(guān)鍵步驟,。之前的研究雖然揭示了一些組蛋白泛素化的機(jī)制，但是并未在H2A去泛素化過(guò)程機(jī)理研究中獲得進(jìn)展,，這一突破性的研究成果目前公布在《自然》雜志上,。
文章的通訊作者是來(lái)自阿拉巴馬大學(xué)的王橫濱（Hengbin Wang，音譯）副教授,，其早年畢業(yè)于河北師范大學(xué),，于中國(guó)農(nóng)業(yè)大學(xué)獲得博士學(xué)位，之后赴日本九州大學(xué)進(jìn)行博士后研究工作,，目前任阿拉巴馬大學(xué)副教授,。
組蛋白翻譯后修飾在染色體結(jié)構(gòu)和功能方面具有十分重要的意義，扮演著調(diào)控者的角色,，這些修飾中的組蛋白泛素化（ubiquitination）主要出現(xiàn)在組蛋白H2A和H2B上,，近期雖然已識(shí)別出組蛋白H2A的泛素化配基在Hox基因沉默和X染色體失活的H2A泛素化過(guò)程中起到了關(guān)鍵作用，但是H2A去泛素化（deubiquitination）過(guò)程中的酶以及H2A去泛素化作用至今并不清楚,。
在這篇文章中,，研究人員報(bào)道了組蛋白H2A,，Ubp-M（也稱(chēng)為USP16）主要泛素化的功能性特征，實(shí)驗(yàn)表明體外Ubp-M接近于核小體底物,，與組蛋白H2A去泛素化特異性相關(guān),，但是體外與體內(nèi)都與H2B無(wú)關(guān)。
值得注意的是,，研究人員敲除了HeLa細(xì)胞中的Ubp-M,，結(jié)果發(fā)現(xiàn)細(xì)胞周期的有絲分裂過(guò)程受到影響，導(dǎo)致細(xì)胞生長(zhǎng)緩慢,，進(jìn)一步研究則揭示Ubp-M引起的H2A去泛素過(guò)程是接下來(lái)的H3上Ser10的磷酸化,，以及細(xì)胞進(jìn)入有絲分裂過(guò)程中染色體分離（chromosome segregation）的必要條件。
而且研究人員也證實(shí)Ubp-M可以通過(guò)H2A去泛素化調(diào)控Hox基因表達(dá),，阻斷Ubp-M的功能會(huì)導(dǎo)致光滑爪蟾（Xenopus laevis）的生長(zhǎng)缺陷,。這些研究識(shí)別出了組蛋白H2A的主要去泛素化過(guò)程，也證明H2A去泛素化是細(xì)胞周期過(guò)程和基因表達(dá)的關(guān)鍵步驟,。
原始出處:
Nature advance online publication 3 October 2007 | doi:10.1038/nature06256; Received 23 May 2007; Accepted 11 September 2007; Published online 3 October 2007
Regulation of cell cycle progression and gene expression by H2A deubiquitination
Heui-Yun Joo1,4, Ling Zhai1,4, Chunying Yang1, Shuyi Nie2, Hediye Erdjument-Bromage3, Paul Tempst3, Chenbei Chang2 & Hengbin Wang1
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Kaul Human Genetics Building 402A, 720 South 20th Street, Birmingham, Alabama 35294, USA
Department of Cell Biology, University of Alabama at Birmingham, MCLM 360, Birmingham, Alabama 35294-0005, USA
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
These authors contributed equally to this work.
Correspondence to: Hengbin Wang1 Correspondence and requests for materials should be addressed to H.W. (Email: [email protected]).
Post-translational histone modifications have important regulatory roles in chromatin structure and function1, 2, 3. One example of such modifications is histone ubiquitination, which occurs predominately on histone H2A and H2B. Although the recent identification of the ubiquitin ligase for histone H2A has revealed important roles for H2A ubiquitination in Hox gene silencing4, 5, 6 as well as in X-chromosome inactivation7, 8, the enzyme(s) involved in H2A deubiquitination and the function of H2A deubiquitination are not known. Here we report the identification and functional characterization of the major deubiquitinase for histone H2A, Ubp-M (also called USP16). Ubp-M prefers nucleosomal substrates in vitro, and specifically deubiquitinates histone H2A but not H2B in vitro and in vivo. Notably, knockdown of Ubp-M in HeLa cells results in slow cell growth rates owing to defects in the mitotic phase of the cell cycle. Further studies reveal that H2A deubiquitination by Ubp-M is a prerequisite for subsequent phosphorylation of Ser 10 of H3 and chromosome segregation when cells enter mitosis. Furthermore, we demonstrate that Ubp-M regulates Hox gene expression through H2A deubiquitination and that blocking the function of Ubp-M results in defective posterior development in Xenopus laevis. This study identifies the major deubiquitinase for histone H2A and demonstrates that H2A deubiquitination is critically involved in cell cycle progression and gene expression.
