大多数癌细胞依赖于升高的端粒酶表达和活性来快速生长和增殖。端粒酶阴性癌细胞,相比之下,通常采用替代延长端粒(ALT)途径来维持端粒。ALT细胞的特征是长且动态的端粒和ALT相关的早幼粒细胞白血病(PML)体(APB)的存在。以前的工作已经表明APBs对ALT途径的重要性,但它们的形成和确切作用仍不清楚。这里,我们证明了一种称为HMBOX1的含有同源异型盒的蛋白质可以直接结合端粒双链DNA并与PML核体缔合。因此,我们将该蛋白TAH1重命名为含有端粒相关同源异型盒的蛋白1。TAH1敲低可显著减少APB的数量,并导致端粒DNA损伤应答信号增加。重要的是,TAH1抑制也显著减少端粒C环的存在,表明ALT活性改变。我们的发现指出,TAH1是调节DNA损伤反应的途径之间的新联系,PML核体,和ALT细胞中的端粒稳态,并提供了解ALT细胞如何独立于端粒酶实现持续生长和增殖。
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.