Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage
Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage
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DOI：
10.1038/ng1506
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发表时间：
2005-02-01
期刊：
影响因子：
30.8
通讯作者：
Meyn, MS
中科院分区：
文献类型：
--
作者：
Bradshaw, PS;Stavropoulos, DJ;Meyn, MS
人类细胞中的DNA损伤监测网络可以激活DNA修复、细胞周期检查点和细胞凋亡，以响应每个基因组(1，2)不到4个双链断裂(DSB)。这些相同的网络容忍端粒，部分原因是TRF2蛋白通过促进端粒末端组织成T环(4-6)而阻止端粒末端识别为DSB 3。我们现在发现，在2 S照射后的人成纤维细胞中，TRF2与光诱导的非端粒DNA中的双链断裂有关。与DSB损伤的常见标记物GammaH2 AX不同，TRF2形成与DSB紧密共存的瞬时焦点。TRF2 DSB反应需要TRF2的基本结构域，而不是它的Myb结构域，并且在缺乏功能的ATM和DNA-PK蛋白激酶、Mre11/Rad50/NBS1复合体和Ku70、WRN和BLM修复蛋白的情况下发生。此外，TRF2的过表达抑制了DSB诱导的ATM信号转导靶标的磷酸化。我们的结果表明，TRF2处于DSB识别和处理的初始阶段，发生在ATM与DSB关联和依赖ATM的DSB响应网络激活之前。
DNA damage surveillance networks in human cells can activate DNA repair, cell cycle checkpoints and apoptosis in response to fewer than four double-strand breaks (DSBs) per genome(1,2). These same networks tolerate telomeres, in part because the protein TRF2 prevents recognition of telomeric ends as DSBs 3 by facilitating their organization into T loops(4-6). We now show that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 s of irradiation. Unlike gammaH2AX, a common marker for DSB damage, TRF2 forms transient foci that colocalize closely with DSBs. The TRF2 DSB response requires the TRF2 basic domain but not its Myb domain and occurs in the absence of functional ATM and DNA-PK protein kinases, MRE11/Rad50/NBS1 complex and Ku70, WRN and BLM repair proteins. Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets. Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network.