Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania.
Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9-1-1 complex in the maintenance of the plastic genome of Leishmania.
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DOI：
10.1093/nar/gky1017
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发表时间：
2018-12-14
影响因子：
14.9
通讯作者：
Tosi LRO
中科院分区：
文献类型：
--
作者：
Damasceno JD;Obonaga R;Silva GLA;Reis-Cunha JL;Duncan SM;Bartholomeu DC;Mottram JC;McCulloch R;Tosi LRO
利什曼原虫属是原生动物寄生虫，其显著的可塑性基因组限制了有效的遗传操作和利什曼病治疗的建立。利什曼原虫在允许变异的同时维持其基因组的策略尚未完全了解。在这里，我们使用DiCre介导的条件性基因缺失来表明，HUS 1，9-1-1（RAD 9-RAD 1-HUS 1）复合物的一个组成部分，是必不可少的，是G2/M检查点所必需的。通过分析HUS 1消融细胞中的全基因组不稳定性，显示HUS 1具有保守作用，通过该作用，其保持基因组稳定性，并且还具有发散作用，通过该作用，其促进基因组变异性。HUS 1的这些作用与整个细胞周期中单链DNA和γ H2 A的形成和分解的不同模式有关。我们的研究结果表明，利什曼原虫9-1-1亚基已经进化到共同选择典型的基因组维持和基因组变异功能。因此，这项研究揭示了HUS 1在平衡利什曼原虫基因组稳定性和传播方面的关键功能。这些发现可能与理解其他病原体和真核生物中基因组维持和可塑性的进化有关。
Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9–1–1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9–1–1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes.
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影响因子：
3.6
作者：
Duncan SM;Myburgh E;Philipon C;Brown E;Meissner M;Brewer J;Mottram JC
通讯作者：
Mottram JC
影响因子：
3.7
作者：
Kelly RS;Lundh T;Porta M;Bergdahl IA;Palli D;Johansson AS;Botsivali M;Vineis P;Vermeulen R;Kyrtopoulos SA;Chadeau-Hyam M;EnviroGenoMarkersProject Consortium
通讯作者：
EnviroGenoMarkersProject Consortium
影响因子：
5.8
作者：
Li, Heng
通讯作者：
Li, Heng
影响因子：
4.5
作者：
Lyndaker AM;Lim PX;Mleczko JM;Diggins CE;Holloway JK;Holmes RJ;Kan R;Schlafer DH;Freire R;Cohen PE;Weiss RS
通讯作者：
Weiss RS
影响因子：
4
作者：
Abdu, Uri;Klovstad, Martha;Schupbach, Trudi
通讯作者：
Schupbach, Trudi