Svotelis Amy, Gévry Nicolas, Gaudreau Luc
Departement de biologie, Faculte des Sciences, Universite de Sherbrooke, Sherbrooke, QCJ1K2R1, Canada.
Biochem Cell Biol. 2009 Feb;87(1):179-88. doi: 10.1139/O08-138.
The mammalian genome is organized into a structure of DNA and proteins known as chromatin. In general, chromatin presents a barrier to gene expression that is regulated by several pathways, namely by the incorporation of histone variants into the nucleosome. In yeast, H2A.Z is an H2A histone variant that is incorporated into nucleosomes as an H2A.Z/H2B dimer by the Swr1 complex and by the SRCAP and p400/Tip60 complexes in mammalian cells. H2A.Z has been associated with the poising of genes for transcriptional activation in the yeast model system, and is essential for development in higher eukaryotes. Recent studies in our laboratory have demonstrated a p400-dependent deposition of H2A.Z at the promoter of p21WAF1/CIP1, a consequence that prevents the activation of the gene by p53, thereby inhibiting p53-dependent replicative senescence, a form of cell-cycle arrest crucial in the prevention of carcinogenic transformation of cells. Moreover, H2A.Z is overexpressed in several different types of cancers, and its overexpression has been associated functionally with the proliferation state of cells. Therefore, we suggest that H2A.Z is an important regulator of gene expression, and its deregulation may lead to the increased proliferation of mammalian cells.
哺乳动物基因组被组织成一种称为染色质的DNA和蛋白质结构。一般来说，染色质对基因表达构成障碍，这是由多种途径调控的，即通过将组蛋白变体掺入核小体来实现。在酵母中，H2A.Z是一种H2A组蛋白变体，在酵母中它通过Swr1复合物被掺入核小体，形成H2A.Z/H2B二聚体，在哺乳动物细胞中则通过SRCAP和p400/Tip60复合物掺入。在酵母模型系统中，H2A.Z与基因转录激活的准备状态有关，并且对高等真核生物的发育至关重要。我们实验室最近的研究表明，p400依赖的H2A.Z在p21WAF1/CIP1启动子处的沉积，这一结果阻止了p53对该基因的激活，从而抑制了p53依赖的复制性衰老，这是一种在防止细胞致癌转化中至关重要的细胞周期阻滞形式。此外，H2A.Z在几种不同类型的癌症中过度表达，其过度表达在功能上与细胞的增殖状态有关。因此，我们认为H2A.Z是基因表达的重要调节因子，其失调可能导致哺乳动物细胞增殖增加。
