Fission yeast Tel1(ATM) and Rad3(ATR) promote telomere protection and telomerase recruitment.
Fission yeast Tel1(ATM) and Rad3(ATR) promote telomere protection and telomerase recruitment.
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DOI：
10.1371/journal.pgen.1000622
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发表时间：
2009-08
期刊：
影响因子：
4.5
通讯作者：
Nakamura TM
中科院分区：
文献类型：
--
作者：
Moser BA;Subramanian L;Khair L;Chang YT;Nakamura TM
在不同的生物中，包括发芽和分裂酵母、拟南芥、果蝇和哺乳动物，ATM和ATR是维持稳定的端粒所必需的。然而，在同时利用端粒保护复合体Shelterin和端粒酶来维持端粒的生物中，缺乏ATM和ATR的细胞端粒不稳定的分子基础尚未完全阐明，如分裂酵母和人类。在这里，我们通过定量染色质免疫沉淀(CHIP)分析证明，Tel1ATM和Rad3ATR激酶的同时丢失导致端粒酶在端粒上的募集缺陷，减少了掩蔽素复合亚单位Ccq1和Tpz1的结合，并增加了RPA和同源重组修复因子与端粒的结合。此外，我们发现Tpz1-Ccq1和端粒酶之间的相互作用在TEL1ΔRAD3Δ细胞中被破坏，端粒酶被认为是端粒酶重新募集到端粒的重要因素。因此，Tel1ATM和Rad3ATR对于保护端粒免受重组和促进端粒酶的募集都是多余的。基于我们目前的发现，我们建议在Tpz1-Ccq1和Tel1ATM/Rad3ATR激酶之间存在一个调控环，以确保在分裂酵母中适当地保护和维持端粒。端粒的稳定维持对于保持基因组的完整性和防止可能导致肿瘤细胞形成的有害突变的积累至关重要。分裂酵母细胞是研究端粒维持机制的一个特别有吸引力的模型系统，因为对端粒维持至关重要的蛋白质在分裂酵母和人类之间高度保守。先前的研究表明，在多种生物体中，检验点激酶ATM(Tel1)和ATR(Rad3)是维持端粒稳定所必需的。在这里，我们研究了缺乏ATM和ATR激酶的分裂酵母细胞端粒功能障碍的分子基础。我们的结果表明，分裂酵母ATM和ATR是冗余地需要促进端粒保护复合体亚单位有效地招募到端粒，这反过来又促进维持端粒所需的端粒酶的招募。人类ATM和ATR激酶可能同样通过促进端粒保护复合体亚单位的募集来促进端粒保护和端粒酶募集。
The checkpoint kinases ATM and ATR are redundantly required for maintenance of stable telomeres in diverse organisms, including budding and fission yeasts, Arabidopsis, Drosophila, and mammals. However, the molecular basis for telomere instability in cells lacking ATM and ATR has not yet been elucidated fully in organisms that utilize both the telomere protection complex shelterin and telomerase to maintain telomeres, such as fission yeast and humans. Here, we demonstrate by quantitative chromatin immunoprecipitation (ChIP) assays that simultaneous loss of Tel1ATM and Rad3ATR kinases leads to a defect in recruitment of telomerase to telomeres, reduced binding of the shelterin complex subunits Ccq1 and Tpz1, and increased binding of RPA and homologous recombination repair factors to telomeres. Moreover, we show that interaction between Tpz1-Ccq1 and telomerase, thought to be important for telomerase recruitment to telomeres, is disrupted in tel1Δ rad3Δ cells. Thus, Tel1ATM and Rad3ATR are redundantly required for both protection of telomeres against recombination and promotion of telomerase recruitment. Based on our current findings, we propose the existence of a regulatory loop between Tel1ATM/Rad3ATR kinases and Tpz1-Ccq1 to ensure proper protection and maintenance of telomeres in fission yeast. Stable maintenance of telomeres is critical to preserve genomic integrity and to prevent accumulation of undesired mutations that might lead to formation of tumor cells. Fission yeast cells serve as a particularly attractive model system to study telomere maintenance mechanisms, since proteins critical for telomere maintenance are highly conserved between fission yeast and humans. Previous studies have shown that the checkpoint kinases ATM (Tel1) and ATR (Rad3) are required for stable maintenance of telomeres in a wide variety of organisms. Here, we investigated the molecular basis for telomere dysfunction in fission yeast cells lacking ATM and ATR kinases. Our results show that fission yeast ATM and ATR are redundantly required to promote efficient recruitment of telomere protection complex subunits to telomeres, which in turn promote recruitment of telomerase needed to maintain telomeres. Human ATM and ATR kinases might similarly promote telomere protection and telomerase recruitment by promoting recruitment of telomere protection complex subunits.
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影响因子：
5.3
作者：
Chahwan, C;Nakamura, TM;Rhind, N
通讯作者：
Rhind, N
影响因子：
4.8
作者：
Miyoshi, T;Sadaie, M;Ishikawa, F
通讯作者：
Ishikawa, F
DOI：
10.1073/pnas.0705497104
发表时间：
2007-08-28
影响因子：
11.1
作者：
Martin, Victoria;Du, Li-Lin;Russell, Paul
通讯作者：
Russell, Paul
影响因子：
64.8
作者：
Cooper, JP;Nimmo, ER;Cech, TR
通讯作者：
Cech, TR
影响因子：
56.9
作者：
Miyoshi, Tomoichiro;Kanoh, Junko;Ishikawa, Fuyuki
通讯作者：
Ishikawa, Fuyuki