Cancer Research Unit, Children's Medical Research Institute, Westmead NSW 2145, Australia.
J Cell Biol. 2012 Dec 10;199(6):893-906. doi: 10.1083/jcb.201207189.
Telomeres in cells that use the recombination-mediated alternative lengthening of telomeres (ALT) pathway elicit a DNA damage response that is partly independent of telomere length. We therefore investigated whether ALT telomeres contain structural abnormalities that contribute to ALT activity. Here we used next generation sequencing to analyze the DNA content of ALT telomeres. We discovered that variant repeats were interspersed throughout the telomeres of ALT cells. We found that the C-type (TCAGGG) variant repeat predominated and created a high-affinity binding site for the nuclear receptors COUP-TF2 and TR4. Nuclear receptors were directly recruited to telomeres and ALT-associated characteristics were induced after incorporation of the C-type variant repeat by a mutant telomerase. We propose that the presence of variant repeats throughout ALT telomeres results from recombination-mediated telomere replication and spreading of variant repeats from the proximal regions of the telomeres and that the consequent binding of nuclear receptors alters the architecture of telomeres to facilitate further recombination.
端粒在使用重组介导的端粒延长替代途径（ALT）的细胞中引发 DNA 损伤反应，该反应部分独立于端粒长度。因此，我们研究了 ALT 端粒是否包含有助于 ALT 活性的结构异常。在这里，我们使用下一代测序来分析 ALT 端粒的 DNA 含量。我们发现变体重复在 ALT 细胞的端粒中散布。我们发现 C 型（TCAGGG）变体重复为主，并为核受体 COUP-TF2 和 TR4 创建了一个高亲和力结合位点。核受体被直接招募到端粒上，并且在突变端粒酶掺入 C 型变体重复后，诱导了 ALT 相关特征。我们提出，变体重复的存在是由于重组介导的端粒复制和变体重复从端粒的近端区域扩散所致，并且随后核受体的结合改变了端粒的结构，以促进进一步的重组。
