Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance
Drosophila ATM and ATR checkpoint kinases control partially redundant pathways for telomere maintenance
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DOI：
10.1073/pnas.0504981102
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发表时间：
2005-10-18
影响因子：
11.1
通讯作者：
Rong, YKS
中科院分区：
文献类型：
--
作者：
Bi, XL;Srikanta, D;Rong, YKS
在高等真核生物中，共济失调毛细血管扩张突变（ATM）和ATM和Rad3相关（ATR）检查点激酶在DNA损伤反应中发挥不同但部分重叠的作用。然而，它们的相互关联的功能还没有被定义为端粒的维护。我们在果蝇中发现，这两种蛋白质控制部分冗余的端粒保护途径：ATM的丢失导致一些端粒的融合，而ATM和ATR的丢失使所有端粒易于融合。ATM控制的途径包括Mre 11和奈梅亨断裂综合征复合物，但不包括Chk2激酶，而ATR调节的途径包括其伴侣ATR相互作用蛋白，但不包括Chk1激酶。这一发现表明，ATM和ATR调节不同的分子事件在端粒相比，DNA损伤的网站。ATM和ATR之间的这种补偿关系与在酵母中观察到的非常相似，尽管在两个模型系统中端粒延伸的生物化学是完全不同的。我们提供的证据表明，无论是加载的端粒帽蛋白和正常的端粒沉默需要ATM和ATR在果蝇，并提出ATM和ATR保护端粒的完整性，通过维护染色质结构，有利于加载的端粒延长，帽，和沉默蛋白。
In higher eukaryotes, the ataxia telangiectasia mutated (ATM) and ATM and Rad3-related (ATR) checkpoint kinases play distinct, but partially overlapping, roles in DNA damage response. Yet their interrelated function has not been defined for telomere maintenance. We discover in Drosophila that the two proteins control partially redundant pathways for telomere protection: the loss of ATM leads to the fusion of some telomeres, whereas the loss of both ATM and ATR renders all telomeres susceptible to fusion. The ATM-controlled pathway includes the Mre11 and Nijmegen breakage syndrome complex but not the Chk2 kinase, whereas the ATR-regulated pathway includes its partner ATR-interacting protein but not the Chk1 kinase. This finding suggests that ATM and ATR regulate different molecular events at the telomeres compared with the sites of DNA damage. This compensatory relationship between ATM and ATR is remarkably similar to that observed in yeast despite the fact that the biochemistry of telomere elongation is completely different in the two model systems. We provide evidence suggesting that both the loading of telomere capping proteins and normal telomeric silencing requires ATM and ATR in Drosophila and propose that ATM and ATR protect telomere integrity by safeguarding chromatin architecture that favors the loading of telomere-elongating, capping, and silencing proteins.