Pif1- and Exo1-dependent nucleases coordinate checkpoint activation following telomere uncapping.
Pif1- and Exo1-dependent nucleases coordinate checkpoint activation following telomere uncapping.
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DOI：
10.1038/emboj.2010.267
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发表时间：
2010-12-01
期刊：
影响因子：
11.4
通讯作者：
Lydall, David
中科院分区：
文献类型：
--
作者：
Dewar, James M.;Lydall, David
在端粒封盖蛋白Cdc13缺失的情况下，出芽酵母端粒被侵蚀，导致检查点阻滞。这项研究表明，被称为端粒酶抑制剂的解旋酶Pif1也与核酸酶Exo1平行，在切除未封盖的端粒中起直接作用。必需的端粒“封顶”蛋白通过抑制DNA损伤反应（DDR）和调节端粒酶的募集，从而将端粒与双链断裂（dsb）区分开来，从而起到防止衰老和癌症的作用。未封顶的端粒和未修复的dsb都能刺激有效的DDR，导致细胞周期阻滞和细胞死亡。利用Cdc13 -1突变在出芽酵母中有条件地“打开”端粒，我们发现端粒封盖蛋白Cdc13保护端粒免受解旋酶Pif1和外切酶Exo1的活性。我们的数据支持无帽端粒DDR的两阶段模型；Pif1和Exo1切除染色体末端< 5kb的端粒DNA，刺激弱检查点激活；切除被Exo1延长了bbbb5 kb，检查点完全激活。Cdc13对端粒酶的募集也至关重要。然而，缺乏Cdc13、Pif1和Exo1的细胞不会衰老，并以依赖端粒酶、Ku和同源重组的方式维持其端粒。因此，在未封顶的端粒上DDR的衰减可以规避对其他必要的端粒封顶蛋白的需求。
In the absence of the telomere capping protein Cdc13, budding yeast telomeres erode, resulting in checkpoint arrest. This study shows that the helicase Pif1, known as a telomerase inhibitor, also has a direct role in the resection of uncapped telomeres, acting in parallel to the nuclease Exo1. Essential telomere ‘capping' proteins act as a safeguard against ageing and cancer by inhibiting the DNA damage response (DDR) and regulating telomerase recruitment, thus distinguishing telomeres from double-strand breaks (DSBs). Uncapped telomeres and unrepaired DSBs can both stimulate a potent DDR, leading to cell cycle arrest and cell death. Using the cdc13-1 mutation to conditionally ‘uncap' telomeres in budding yeast, we show that the telomere capping protein Cdc13 protects telomeres from the activity of the helicase Pif1 and the exonuclease Exo1. Our data support a two-stage model for the DDR at uncapped telomeres; Pif1 and Exo1 resect telomeric DNA <5 kb from the chromosome end, stimulating weak checkpoint activation; resection is extended >5 kb by Exo1 and full checkpoint activation occurs. Cdc13 is also crucial for telomerase recruitment. However, cells lacking Cdc13, Pif1 and Exo1, do not senesce and maintain their telomeres in a manner dependent upon telomerase, Ku and homologous recombination. Thus, attenuation of the DDR at uncapped telomeres can circumvent the need for otherwise-essential telomere capping proteins.
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影响因子：
4.5
作者：
Chung WH;Zhu Z;Papusha A;Malkova A;Ira G
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DOI：
10.1126/science.1170633
发表时间：
2009-11-13
期刊：
Science (New York, N.Y.)
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