Trypanosoma brucei Orc1 is essential for nuclear DNA replication and affects both VSG silencing and VSG switching.
Trypanosoma brucei Orc1 is essential for nuclear DNA replication and affects both VSG silencing and VSG switching.
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DOI：
10.1111/mmi.12093
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发表时间：
2013-01
影响因子：
3.6
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Benmerzouga I;Concepción-Acevedo J;Kim HS;Vandoros AV;Cross GA;Klingbeil MM;Li B
起点识别复合体 (ORC) 与复制起点的结合对于 DNA 复制的启动至关重要，但 ORC 在 DNA 复制之外具有非必需功能，包括异染色质基因沉默和端粒维持。布氏锥虫是一种引起人类非洲锥虫病的原生动物寄生虫，它利用抗原变异作为主要毒力机制，通过以单等位基因的方式表达其主要表面抗原——变异表面糖蛋白（VSG）来逃避宿主的免疫攻击。已在 T. brucei 中鉴定出 Orc1/Cdc6 同源物，但其在 DNA 复制中的作用尚未得到直接证实，并且其在 VSG 抑制或转换中的潜在参与尚未得到彻底研究。在这项研究中，我们证明 TbOrc1 对于哺乳动物感染性血流和采采蝇原循环形式（BF 和 PF）中的核 DNA 复制至关重要。 TbOrc1 的缺失导致 BF 和 PF 中端粒相关的沉默 VSG 去抑制，并增加 VSG 转换，特别是通过原位转录转换机制。 TbOrc1 与端粒重复相关，但似乎独立于两种已知的布氏锥虫端粒蛋白 TbRAP1 和 TbTRF。我们得出结论，TbOrc1 在 DNA 复制中具有保守功能，并且也是控制端粒相关 VSG 表达和 VSG 转换所必需的。
Binding of the Origin Recognition Complex (ORC) to replication origins is essential for initiation of DNA replication, but ORC has non-essential functions outside of DNA replication, including in heterochromatic gene silencing and telomere maintenance. Trypanosoma brucei, a protozoan parasite that causes human African trypanosomiasis, uses antigenic variation as a major virulence mechanism to evade the host’s immune attack by expressing its major surface antigen, the Variant Surface Glycoprotein (VSG), in a monoallelic manner. An Orc1/Cdc6 homolog has been identified in T. brucei, but its role in DNA replication has not been directly confirmed and its potential involvement in VSG repression or switching has not been thoroughly investigated. In this study, we show that TbOrc1 is essential for nuclear DNA replication in mammalian-infectious bloodstream and tsetse procyclic forms (BF and PF). Depletion of TbOrc1 resulted in derepression of telomere-linked silent VSGs in both BF and PF, and increased VSG switching particularly through the in-situ transcriptional switching mechanism. TbOrc1 associates with telomere repeats but appears to do so independently of two known T. brucei telomere proteins, TbRAP1 and TbTRF. We conclude that TbOrc1 has conserved functions in DNA replication and is also required to control telomere-linked VSG expression and VSG switching.
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