The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells
The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells
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端粒相关同源盒蛋白 TAH1/HMBOX1 参与 ALT 细胞的端粒维持
DOI：
10.1242/jcs.128512
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发表时间：
2013-09-01
影响因子：
4
通讯作者：
Zhou Songyang
中科院分区：
文献类型：
--
作者：
Feng, Xuyang;Luo, Zhenhua;Zhou Songyang
摘要 大多数癌细胞依赖端粒酶表达和活性的升高来快速生长和增殖。相比之下，端粒酶阴性的癌细胞通常采用替代性端粒延长 (ALT) 途径来维持端粒。 ALT 细胞的特征是长且动态的端粒以及 ALT 相关的早幼粒细胞白血病 (PML) 小体 (APB) 的存在。先前的工作已经表明 APB 对 ALT 通路的重要性，但它们的形成和确切作用仍不清楚。在这里，我们证明了一种名为 HMBOX1 的含有同源盒的蛋白质可以直接结合端粒双链 DNA 并与 PML 核体结合。因此，我们将该蛋白重新命名为端粒相关同源框蛋白 1。TAH1 敲低显着减少了 APB 的数量，并导致端粒处 DNA 损伤反应信号的增加。重要的是，TAH1 抑制也显着减少了端粒 C 环的存在，表明 ALT 活性发生了改变。我们的研究结果表明，TAH1 是 ALT 细胞中调节 DNA 损伤反应、PML 核体和端粒稳态的途径之间的新联系，并为 ALT 细胞如何独立于端粒酶实现持续生长和增殖提供了见解。
Summary The majority of cancer cells rely on elevated telomerase expression and activity for rapid growth and proliferation. Telomerase-negative cancer cells, by contrast, often employ the alternative lengthening of telomeres (ALT) pathway to maintain telomeres. ALT cells are characterized by long and dynamic telomeres and the presence of ALT-associated promyelocytic leukemia (PML) bodies (APBs). Previous work has shown the importance of APBs to the ALT pathway, but their formation and precise role remain unclear. Here, we demonstrate that a homeobox-containing protein known as HMBOX1 can directly bind telomeric double-stranded DNA and associate with PML nuclear bodies. Hence, we renamed this protein TAH1 for telomere-associated homeobox-containing protein 1. TAH1 knockdown significantly reduced the number of APBs and led to an increase in DNA damage response signals at telomeres. Importantly, TAH1 inhibition also notably reduced the presence of telomere C-circles, indicating altered ALT activity. Our findings point to TAH1 as a novel link between pathways that regulate DNA damage responses, PML nuclear bodies, and telomere homeostasis in ALT cells, and provide insight into how ALT cells may achieve sustained growth and proliferation independent of the telomerase.