Telomere length affects the frequency and mechanism of antigenic variation in Trypanosoma brucei.
Telomere length affects the frequency and mechanism of antigenic variation in Trypanosoma brucei.
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DOI：
10.1371/journal.ppat.1002900
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Papavasiliou FN
中科院分区：
文献类型：
--
作者：
Hovel-Miner GA;Boothroyd CE;Mugnier M;Dreesen O;Cross GA;Papavasiliou FN
布鲁氏锥虫是抗原变异和免疫反应逃避的大师。利用1000多个不同的表面糖蛋白编码基因(VSG)的基因组库，布氏毛滴虫可以通过从一个VSG的表达切换到另一个VSG的表达来改变其蛋白质外壳。每个活性VSG仅在大约15个亚端粒中的一个亚端粒位点上单等位表达。VSG表达的转换有三种主要机制，其中最重要的机制是通过复制基因转换(GC)实现含有DNA的VSG的非互惠交换。布鲁氏锥虫是如何协调其复杂的转换机制的还有待阐明。最近的研究表明，活性部位的外源性DNA断裂可以启动基于GC的开关，但在自然条件下启动开关的DNA损伤的来源尚不清楚。在这里，我们研究了端粒长度直接影响VSG开关的假设。我们证明，端粒短的端粒酶缺陷菌株比基因相同的长端粒菌株更频繁地进行切换，并且，当端粒较短时，GC优先发生切换。我们的数据支持这样的假设，即VSG表达活性部位的短端粒会导致亚端粒DNA断裂的增加，这可以启动基于GC的开关。除了它们对布鲁氏毛滴虫和端粒生物学的意义外，这里提出的发现还对许多不同的病原体有意义，这些病原体在亚端粒区域组织它们的抗原基因。各种各样的人类病原体(包括细菌、真菌和寄生虫)会改变它们细胞表面的蛋白质，以逃避宿主的免疫反应。这一过程被称为抗原变异，依赖于基因组中一系列变异蛋白编码基因，以及生物体准确地从一个变异基因表达切换到另一个变异基因的能力。这些变异基因的多样性及其表达所需机制的一个共同主题是，它们通常位于染色体末端附近。染色体末端受到称为端粒的结构的保护。端粒附近的区域被称为亚端粒，通常被认为是相对不稳定的DNA位点。因此，耐人寻味的是，依赖抗原变异生存的生物体会在这些位置组织它们关键的生存基因。布鲁氏锥虫是研究抗原变异的模式生物。这种单细胞寄生虫是非洲昏睡病的病原体，具有无与伦比的多样性，只能在特定的亚端粒位点表达。在这里，我们使用布氏毛滴虫模型的力量来研究端粒长度对抗原变异的影响。
Trypanosoma brucei is a master of antigenic variation and immune response evasion. Utilizing a genomic repertoire of more than 1000 Variant Surface Glycoprotein-encoding genes (VSGs), T. brucei can change its protein coat by “switching” from the expression of one VSG to another. Each active VSG is monoallelically expressed from only one of approximately 15 subtelomeric sites. Switching VSG expression occurs by three predominant mechanisms, arguably the most significant of which is the non-reciprocal exchange of VSG containing DNA by duplicative gene conversion (GC). How T. brucei orchestrates its complex switching mechanisms remains to be elucidated. Recent work has demonstrated that an exogenous DNA break in the active site could initiate a GC based switch, yet the source of the switch-initiating DNA lesion under natural conditions is still unknown. Here we investigated the hypothesis that telomere length directly affects VSG switching. We demonstrate that telomerase deficient strains with short telomeres switch more frequently than genetically identical strains with long telomeres and that, when the telomere is short, switching preferentially occurs by GC. Our data supports the hypothesis that a short telomere at the active VSG expression site results in an increase in subtelomeric DNA breaks, which can initiate GC based switching. In addition to their significance for T. brucei and telomere biology, the findings presented here have implications for the many diverse pathogens that organize their antigenic genes in subtelomeric regions. A broad array of human pathogens (including bacteria, fungi and parasites) vary the proteins on their cell surface to escape the immune response of their hosts. This process, called antigenic variation, relies on a repertoire of variant protein encoding genes in the genome and the organism's ability to accurately switch from the expression of one variant gene to another. A common theme in both the diversification of these variant genes and the mechanisms required for their expression is that they are often located near the ends of chromosomes. The ends of chromosomes are protected by structures called telomeres. Regions near the telomere are referred to as subtelomeric and are commonly thought to be comparatively unstable DNA sites. It is therefore intriguing that organisms that rely on antigenic variation for survival would organize their critical survival genes in these sites. Trypanosoma brucei is a model organism for the study of antigenic variation. The causative agent of African sleeping sickness, this unicellular parasite possesses an antigenic repertoire of unparalleled diversity, which can only be expressed from specific subtelomeric sites. Here we use the power of the T. brucei model to investigate the effect of telomere length on antigenic variation.
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DOI：
10.1038/nrmicro2145
发表时间：
2009-07
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
JOHNSON, PJ;BORST, P
通讯作者：
BORST, P
影响因子：
1.5
作者：
Horn, D;Cross, GAM
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Cross, GAM
影响因子：
14.9
作者：
DELANGE, T;KOOTER, JM;BORST, P
通讯作者：
BORST, P
影响因子：
1.5
作者：
Berriman, M;Hall, N;Rudenko, G
通讯作者：
Rudenko, G