Nature：王横滨等—组蛋白H2A去泛素化过程机理研究
来自阿拉巴马州大学生物化学与分子遗传学系，细胞生物学系，纪念斯隆－凯特琳癌症中心（Memorial Sloan -Kettering Cancer Center）的研究人员识别出了组蛋白H2A的主要去泛素化（deubiquitination）过程，也证明H2A去泛素化是细胞周期和基因表达的关键步骤。之前的研究虽然揭示了一些组蛋白泛素化的机制，但是并未在H2A去泛素化过程机理研究中获得进展，这一突破性的研究成果目前公布在《自然》杂志上。
文章的通讯作者是来自阿拉巴马大学的王横滨（Hengbin Wang，音译）副教授，其早年毕业于河北师范大学，于中国农业大学获得博士学位，之后赴日本九州大学进行博士后研究工作，目前任阿拉巴马大学副教授。
组蛋白翻译后修饰在染色体结构和功能方面具有十分重要的意义，扮演着调控者的角色，这些修饰中的组蛋白泛素化（ubiquitination）主要出现在组蛋白H2A和H2B上，近期虽然已识别出组蛋白H2A的泛素化配基在Hox基因沉默和X染色体失活的H2A泛素化过程中起到了关键作用，但是H2A去泛素化（deubiquitination）过程中的酶以及H2A去泛素化作用至今并不清楚。
在这篇文章中，研究人员报道了组蛋白H2A，Ubp-M（也称为USP16）主要泛素化的功能性特征，实验表明体外Ubp-M接近于核小体底物，与组蛋白H2A去泛素化特异性相关，但是体外与体内都与H2B无关。
值得注意的是，研究人员敲除了HeLa细胞中的Ubp-M，结果发现细胞周期的有丝分裂过程受到影响，导致细胞生长缓慢，进一步研究则揭示Ubp-M引起的H2A去泛素过程是接下来的H3上Ser10的磷酸化，以及细胞进入有丝分裂过程中染色体分离（chromosome segregation）的必要条件。
而且研究人员也证实Ubp-M可以通过H2A去泛素化调控Hox基因表达，阻断Ubp-M的功能会导致光滑爪蟾（Xenopus laevis）的生长缺陷。这些研究识别出了组蛋白H2A的主要去泛素化过程，也证明H2A去泛素化是细胞周期过程和基因表达的关键步骤。
原始出处:
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: hbwang@uab.edu).
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.
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