Rai Rekha, Chang Sandy
Department of Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Methods Mol Biol. 2011;735:145-50. doi: 10.1007/978-1-61779-092-8_14.
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the inhibition of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant negative mutant TPP1(ΔRD), can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)." Induction of TIFs at telomeres provides an opportunity to quantify the extent of telomere dysfunction and monitor the signaling pathways.
端粒功能障碍，可通过端粒DNA的复制性损耗或由于抑制端粒保护蛋白组分而产生，被DNA损伤修复（DDR）途径识别为DNA双链断裂（DSB）。这导致DNA损伤检查点传感器的激活，包括Mre11-Rad50-Nbs1（MRN）复合物、γ-H2AX和53BP1，ATM和ATR信号转导激酶以及下游效应物，包括Chk1、Chk2和p53。通过完全缺失TRF2或表达显性负性突变体TPP1（ΔRD）在功能失调的端粒处产生的强大DNA损伤反应信号，可通过它们与γ-H2AX和53BP1的结合形成“端粒功能障碍诱导灶（TIFs）”来检测。端粒处TIFs的诱导提供了一个机会来量化端粒功能障碍的程度并监测信号通路。
