DNA damage foci at dysfunctional telomeres
DNA damage foci at dysfunctional telomeres
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DOI：
10.1016/s0960-9822(03)00542-6
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发表时间：
2003-09-02
期刊：
影响因子：
9.2
通讯作者：
de Lange, T
中科院分区：
文献类型：
--
作者：
Takai, H;Smogorzewska, A;de Lange, T
我们报告的细胞学和遗传学数据表明，端粒功能障碍诱导哺乳动物细胞的DNA损伤反应。通过抑制TRF 2产生的功能失调的未加帽的端粒与DNA损伤反应因子如53 BP 1、gamma-H2 AX、Rad 17、ATM和Mre 11相关。我们将端粒相关DNA损伤因子的结构域称为端粒功能障碍诱导的病灶（TIF）。在PI 3激酶抑制剂咖啡因和渥曼青霉素的存在下，53 BP 1在未加帽的端粒上的积累减少，这会影响ATM、ATR和DNA-PK。相比之下，Mre 11 TIF对咖啡因有抵抗力，这与Mre 11对电离辐射反应的先前发现一致。A-T细胞具有减弱的53 BP 1 TIF应答，表明ATM激酶是该途径的主要转导子。然而，在没有ATM的情况下，TRF 2抑制仍然诱导TIF和衰老，指向第二个ATM非依赖性途径。我们的结论是，端粒功能障碍的细胞反应是由蛋白质，也控制DNA损伤反应。TIF代表了一种新的工具，用于评估端粒状态的正常和恶性细胞怀疑窝藏功能失调的端粒。此外，通过TRF 2抑制诱导TIF提供了在明确定义的物理标记病变的背景下研究DNA损伤反应的机会。
We report cytologic and genetic data indicating that telomere dysfunction induces a DNA damage response in mammalian cells. Dysfunctional, uncapped telomeres, created through inhibition of TRF2, became associated with DNA damage response factors, such as 53BP1, gamma-H2AX, Rad17, ATM, and Mre11. We refer to the domain of telomere-associated DNA damage factors as a Telomere Dysfunction-induced Focus (TIF). The accumulation of 53BP1 on uncapped telomeres was reduced in the presence of the PI3 kinase inhibitors caffeine and wortmannin, which affect ATM, ATR, and DNA-PK. By contrast, Mre11 TIFs were resistant to caffeine, consistent with previous findings on the Mre11 response to ionizing radiation. A-T cells had a diminished 53BP1 TIF response, indicating that the ATM kinase is a major transducer of this pathway. However, in the absence of ATM, TRF2 inhibition still induced TIFs and senescence, pointing to a second ATM-independent pathway. We conclude that the cellular response to telomere dysfunction is governed by proteins that also control the DNA damage response. TIFs represent a new tool for evaluating telomere status in normal and malignant cells suspected of harboring dysfunctional telomeres. Furthermore, induction of TIFs through TRF2 inhibition provides an opportunity to study the DNA damage response within the context of well-defined, physically marked lesions.