Telomere end processing and telomere stability maintenance in trypanosomes

锥虫的端粒末端加工和端粒稳定性维持

基本信息

  • 批准号:
    10503111
  • 负责人:
  • 金额:
    $ 29.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-05 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary Telomere, the protein/DNA complex at the chromosome end, is essential for keeping eukaryotic cells proliferative. Conventional DNA polymerases cannot fully replicate the linear DNA ends, and most eukaryotes use telomerase to synthesize the telomere G-rich strand de novo. The terminal telomere G-rich 3’ overhang (G3OH) is essential for telomerase-mediated G-strand synthesis and formation of the T-loop structure that is critical for protection of the natural chromosome ends from illegitimate DNA processes. In addition, the length of G3OH needs to be regulated in order to avoid excessive telomeric recombination. Generation of the telomere G3OH involves resection of the telomere 5’ end by exonucleases after the conventional DNA replication, G- strand synthesis by telomerase, and C-strand filled-in. In higher eukaryotes, these telomere end processes are regulated by OB fold-containing telomere ssDNA-binding proteins, which are absent in the kinetoplastid parasite Trypanosoma brucei. Rather, we have found that T. brucei PolIE, a telomere protein and an A family DNA polymerase, suppresses telomerase-mediated G-strand extension, helps ensure proper telomere C-strand synthesis, and suppresses telomeric recombination. T. brucei causes sleeping sickness in humans and regularly switches its major surface antigen, VSG, to achieve immune evasion. VSGs are monoallelically expressed exclusively from loci immediately upstream of the telomere. We have shown that telomere proteins not only are essential for T. brucei cell proliferation but also regulate VSG monoallelic expression and switching. However, other than the fact that telomerase can synthesize the telomere G-strand DNA, mechanisms of telomere end processing and its regulation are poorly understood in T. brucei. In this project, we aim to investigate mechanisms of T. brucei telomere end processing regulation and telomere stability maintenance. In Aim 1, we will investigate how PolIE suppresses the telomerase action and whether it also affects the ending nucleotides of the two telomere strands. The telomere C-strand fill-in in T. brucei presumably requires a DNA polymerase. Since PolIE is a DNA polymerase, in Aim 2.1, we will test whether its DNA polymerase domain is critical for its role in telomere end processing regulation. We have also identified Primase-Polymerase-like protein 2 (PPL2, with a translesion DNA synthesis activity) as a telomere protein and found that PPL2 depletion dramatically elongates the telomere G3OH length. In Aim 2.2, we will investigate whether PPL2 is important for telomere C-strand fill-in and whether this function is PolIE-dependent. T. brucei does not have the non- homologous end joining (NHEJ) machinery, while dysfunctional telomeres are frequently fused through NHEJ in higher eukaryotes. In Aim 3, we will investigate whether homologous recombination and Microhomology- mediated end joining are major pathways for telomeric recombination in WT and PolIE-depleted cells, which will help reveal illegitimate processes that threaten the natural chromosome ends in T. brucei. Our studies will help us better understand the telomere protein evolution and contribute to future development of anti-parasite agents.
项目总结

项目成果

期刊论文数量(0)
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Bibo Li其他文献

Bibo Li的其他文献

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{{ truncateString('Bibo Li', 18)}}的其他基金

Mechanisms of how Trypanosoma brucei TRF maintains telomere integrity
布氏锥虫 TRF 维持端粒完整性的机制
  • 批准号:
    10622535
  • 财政年份:
    2022
  • 资助金额:
    $ 29.7万
  • 项目类别:
Mechanisms of how Trypanosoma brucei TRF maintains telomere integrity
布氏锥虫 TRF 维持端粒完整性的机制
  • 批准号:
    10526882
  • 财政年份:
    2022
  • 资助金额:
    $ 29.7万
  • 项目类别:
Telomere end processing and telomere stability maintenance in trypanosomes
锥虫的端粒末端加工和端粒稳定性维持
  • 批准号:
    10677878
  • 财政年份:
    2022
  • 资助金额:
    $ 29.7万
  • 项目类别:
Identify 70 bp repeat-associated chromatin components by End-targeting Proteomics of Isolated Chromatin segments (PICh) and initiate their functional characterization
通过分离染色质片段 (PICh) 的末端靶向蛋白质组学鉴定 70 bp 重复相关染色质成分,并启动其功能表征
  • 批准号:
    10417263
  • 财政年份:
    2021
  • 资助金额:
    $ 29.7万
  • 项目类别:
Identify 70 bp repeat-associated chromatin components by End-targeting Proteomics of Isolated Chromatin segments (PICh) and initiate their functional characterization
通过分离染色质片段 (PICh) 的末端靶向蛋白质组学鉴定 70 bp 重复相关染色质成分,并启动其功能表征
  • 批准号:
    10293165
  • 财政年份:
    2021
  • 资助金额:
    $ 29.7万
  • 项目类别:
Characterization of Trypanosome telomere complex
锥虫端粒复合物的表征
  • 批准号:
    7849189
  • 财政年份:
    2009
  • 资助金额:
    $ 29.7万
  • 项目类别:
Characterization of Trypanosome telomere complex
锥虫端粒复合物的表征
  • 批准号:
    7335623
  • 财政年份:
    2007
  • 资助金额:
    $ 29.7万
  • 项目类别:
Characterization of Trypanosome telomere complex
锥虫端粒复合物的表征
  • 批准号:
    7211023
  • 财政年份:
    2007
  • 资助金额:
    $ 29.7万
  • 项目类别:
Characterize functions of T. brucei RAP1 and TRF in antigenic variation and telom
表征 T. brucei RAP1 和 TRF 在抗原变异和端粒中的功能
  • 批准号:
    8107285
  • 财政年份:
    2007
  • 资助金额:
    $ 29.7万
  • 项目类别:
Characterize functions of T. brucei RAP1 and TRF in antigenic variation and telom
表征 T. brucei RAP1 和 TRF 在抗原变异和端粒中的功能
  • 批准号:
    8603220
  • 财政年份:
    2007
  • 资助金额:
    $ 29.7万
  • 项目类别:

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蛋白酶体的催化核心作为治疗非洲人类锥虫病的药物靶点
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