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一种假定的布氏锥虫跨损伤 DNA 聚合酶的基因组维护功能包括端粒结合和在抗原变异中的作用。

Genome maintenance functions of a putative Trypanosoma brucei translesion DNA polymerase include telomere association and a role in antigenic variation.

机构信息

The Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.

Department of Cell & Developmental Biology, Biocenter, University of Würzburg, Würzburg, Germany.

出版信息

Nucleic Acids Res. 2020 Sep 25;48(17):9660-9680. doi: 10.1093/nar/gkaa686.

Abstract

Maintenance of genome integrity is critical to guarantee transfer of an intact genome from parent to offspring during cell division. DNA polymerases (Pols) provide roles in both replication of the genome and the repair of a wide range of lesions. Amongst replicative DNA Pols, translesion DNA Pols play a particular role: replication to bypass DNA damage. All cells express a range of translesion Pols, but little work has examined their function in parasites, including whether the enzymes might contribute to host-parasite interactions. Here, we describe a dual function of one putative translesion Pol in African trypanosomes, which we now name TbPolIE. Previously, we demonstrated that TbPolIE is associated with telomeric sequences and here we show that RNAi-mediated depletion of TbPolIE transcripts results in slowed growth, altered DNA content, changes in cell morphology, and increased sensitivity to DNA damaging agents. We also show that TbPolIE displays pronounced localization at the nuclear periphery, and that its depletion leads to chromosome segregation defects and increased levels of endogenous DNA damage. Finally, we demonstrate that TbPolIE depletion leads to deregulation of telomeric variant surface glycoprotein genes, linking the function of this putative translesion DNA polymerase to host immune evasion by antigenic variation.

摘要

维持基因组完整性对于保证细胞分裂过程中亲代到子代的完整基因组传递至关重要。DNA 聚合酶(Pols)在基因组复制和多种损伤修复中发挥作用。在复制 DNA Pols 中,跨损伤 DNA Pols 发挥了特别的作用:复制以绕过 DNA 损伤。所有细胞都表达一系列跨损伤 Pols,但很少有研究检查它们在寄生虫中的功能,包括这些酶是否可能有助于宿主-寄生虫相互作用。在这里,我们描述了一种在非洲锥虫中可能的跨损伤 Pol 的双重功能,我们现在将其命名为 TbPolIE。此前,我们证明了 TbPolIE 与端粒序列相关,在这里我们表明,RNAi 介导的 TbPolIE 转录本耗竭导致生长缓慢、DNA 含量改变、细胞形态变化以及对 DNA 损伤剂的敏感性增加。我们还表明,TbPolIE 在核周呈现明显的定位,其耗竭导致染色体分离缺陷和内源性 DNA 损伤水平增加。最后,我们证明 TbPolIE 耗竭导致端粒变异表面糖蛋白基因的失调,将这种假定的跨损伤 DNA 聚合酶的功能与抗原变异引起的宿主免疫逃避联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd19/7515707/aac9964bb594/gkaa686fig1.jpg

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