Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Memorial University Medical Center, Savannah, Georgia 31404, USA.
Mol Cancer Res. 2013 Jun;11(6):557-67. doi: 10.1158/1541-7786.MCR-13-0013. Epub 2013 Mar 15.
Telomere maintenance is an essential characteristic of cancer cells, most commonly achieved by activation of telomerase. Telomeres can also be maintained by a recombination-based mechanism, alternative lengthening of telomeres (ALT). Cells using ALT are characterized by the presence of ALT-associated promyelocytic leukemia (PML) bodies (APB), long, heterogeneously sized telomeres, extrachromosomal telomeric circular DNA, and elevated telomeric recombination. Consistent with other reports, we found that liposarcomas containing APBs, but lacking telomerase expression, always contained C-rich circles (C-circles), and these C-circles were never present in the absence of APBs, indicating a tight link between these features in ALT cells. However, a rare subgroup of tumors showing evidence of telomere maintenance by both telomerase and ALT did not contain C-circles. To test the hypothesis that telomerase expression disrupts the tight link between APBs and C-circles, we used ALT cell lines that were engineered to express telomerase. Introduction of telomerase activity in these ALT cells resulted in, on average, shorter telomeres with retention of APBs. However, at high passage, the level of C-circles was significantly reduced, which was paralleled by a switch from C-strand overhangs to G-strand overhangs. We propose that by extending critically short telomeres in these cells, telomerase is disrupting a key step in the ALT pathway necessary for production and/or maintenance of C-circles.
端粒维持是癌细胞的一个重要特征，通常通过端粒酶的激活来实现。端粒也可以通过基于重组的机制来维持，即端粒的替代性延长（ALT）。使用 ALT 的细胞的特征是存在 ALT 相关早幼粒细胞白血病（PML）体（APB）、长的、异质大小的端粒、染色体外端粒环状 DNA 和升高的端粒重组。与其他报道一致，我们发现含有 APB 但缺乏端粒酶表达的脂肪肉瘤总是含有富含 C 的环状 DNA（C 环），并且在没有 APB 的情况下，这些 C 环从未出现过，这表明在 ALT 细胞中这些特征之间存在紧密联系。然而，少数证据表明，肿瘤通过端粒酶和 ALT 都能维持端粒，但并不含有 C 环。为了验证端粒酶表达破坏 APB 和 C 环之间紧密联系的假设，我们使用了经过工程改造表达端粒酶的 ALT 细胞系进行测试。在这些 ALT 细胞中引入端粒酶活性平均导致端粒变短，但 APB 仍保留。然而，在高传代时，C 环的水平显著降低，这与 C 链突出端到 G 链突出端的转变相平行。我们提出，通过延长这些细胞中临界短的端粒，端粒酶破坏了 ALT 途径中产生和/或维持 C 环所必需的关键步骤。
