M. E. Müller Institute for Structural Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
J Cell Sci. 2010 Jun 1;123(Pt 11):1931-9. doi: 10.1242/jcs.065938. Epub 2010 May 11.
BRE1 encodes an E3 ubiquitin protein ligase that is required for the ubiquitylation of histone H2B at lysine 123 (K123). Ubiquitylation of this histone residue is involved in a variety of cellular processes including gene activation and gene silencing. Abolishing histone H2B ubiquitylation also confers X-ray sensitivity and abrogates checkpoint activation after DNA damage. Here we show that Saccharomyces cerevisiae Bre1p exhibits anti-apoptotic activity in yeast and that this is linked to histone H2B ubiquitylation. We found that enhanced levels of Bre1p protect from hydrogen-peroxide-induced cell death, whereas deletion of BRE1 enhances cell death. Moreover, cells lacking Bre1p show reduced lifespan during chronological ageing, a physiological apoptotic condition in yeast. Importantly, the resistance against apoptosis is conferred by histone H2B ubiquitylation mediated by the E3 ligase activity of Bre1p. Furthermore, we found that the death of Deltabre1 cells depends on the yeast caspase Yca1p, because Deltabre1 cells exhibit increased caspase activity when compared with wild-type cells, and deletion of YCA1 leads to reduced apoptosis sensitivity of cells lacking Bre1p.
BRE1 编码一种 E3 泛素蛋白连接酶，该酶对于组蛋白 H2B 赖氨酸 123（K123）的泛素化是必需的。这种组蛋白残基的泛素化参与了多种细胞过程，包括基因激活和基因沉默。组蛋白 H2B 泛素化的消除也赋予了 X 射线敏感性，并在 DNA 损伤后取消了检查点激活。在这里，我们表明酿酒酵母 Bre1p 在酵母中表现出抗细胞凋亡活性，并且这与组蛋白 H2B 泛素化有关。我们发现增强的 Bre1p 水平可保护酵母免受过氧化氢诱导的细胞死亡，而 BRE1 的缺失则增强了细胞死亡。此外，缺乏 Bre1p 的细胞在酵母的生物钟老化过程中表现出寿命缩短，这是一种生理性的凋亡状态。重要的是，由 Bre1p 的 E3 连接酶活性介导的组蛋白 H2B 泛素化赋予了对细胞凋亡的抗性。此外，我们发现 Deltabre1 细胞的死亡依赖于酵母半胱氨酸天冬氨酸蛋白酶 Yca1p，因为与野生型细胞相比，Deltabre1 细胞的 Caspase 活性增加，并且缺失 YCA1 导致缺乏 Bre1p 的细胞的细胞凋亡敏感性降低。
