Regulation of antigenic variation by a DOT1B/RNaseH2 complex in Trypanosoma brucei

布氏锥虫 DOT1B/RNaseH2 复合物对抗原变异的调节

• 批准号: 430676033
• 负责人: Professor Dr. Christian Janzen
• 金额: --
• 依托单位: Lehrstuhl für Zell- und Entwicklungsbiologie (Zoologie I)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/430676033?language=en
• 关键词: Regulation; antigenic; variation; DOT1B; RNaseH2

Post-translational modifications of chromatin regulate many important biological processes such as replication, DNA repair and cell cycle control. We are interested in how the unicellular, eukaryotic parasite Trypanosoma brucei uses chromatin-based mechanisms to regulate antigenic variation, one of its most important strategies to evade the host immune response. Antigenic variation is based on monoallelic expression of a variant surface glycoprotein (VSG), which forms a dense coat on the parasite’s surface. The parasites escape the host immune response by periodically switching the expressed VSG. The exact mechanisms, however, which mediate these switching events are still elusive.We are specifically interested in the function of histone methylation by a member of the Dot1 family of histone methyltransferases during this process. Dot1 (disruptor of telomeric silencing) was initially discovered in yeast in a genetic screen for genes whose over-expression or deletion caused derepression of telomeric genes. We recently discovered that DOT1B, one of the two homologues in trypanosomes, interacts with the ribonuclease RNaseH2 protein complex, which removes DNA/RNA-hybrids, so called R-loops. Interestingly, loss of RNaseH2 activity in trypanosomes causes accumulation of R-loops and DNA damage, which leads to altered VSG expression. We want to elucidate the function of the DOT1B/RNAseH2 complex in trypanosomes. In addition to general function in genome integrity maintenance, we specifically want to test the hypothesis that the DOT1B/RNAseH2 complex may be involved in VSG regulation.

染色质的翻译后修饰调节许多重要的生物过程，例如复制、DNA 修复和细胞周期控制。我们感兴趣的是单细胞真核寄生虫布氏锥虫如何利用基于染色质的机制来调节抗原变异，这是其逃避宿主免疫反应的最重要策略之一。抗原变异基于变异表面糖蛋白（VSG）的单等位基因表达，它在寄生虫表面形成致密的外壳。寄生虫通过定期切换表达的 VSG 来逃避宿主的免疫反应。然而，介导这些转换事件的确切机制仍然难以捉摸。我们对组蛋白甲基转移酶 Dot1 家族成员在此过程中的组蛋白甲基化功能特别感兴趣。 Dot1（端粒沉默破坏者）最初是在酵母中发现的，用于筛选过度表达或缺失导致端粒基因去抑制的基因。我们最近发现，锥虫中的两个同源物之一 DOT1B 与核糖核酸酶 RNaseH2 蛋白复合物相互作用，从而去除 DNA/RNA 杂交体，即所谓的 R 环。有趣的是，锥虫中 RNaseH2 活性的丧失会导致 R 环的积累和 DNA 损伤，从而导致 VSG 表达的改变。我们想要阐明 DOT1B/RNAseH2 复合物在锥虫中的功能。除了维持基因组完整性的一般功能外，我们还特别想测试 DOT1B/RNAseH2 复合物可能参与 VSG 调节的假设。