Huang Chenhui, Jia Pingping, Chastain Megan, Shiva Olga, Chai Weihang
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, PO BOX 1495, Spokane, WA 99210, United States.
Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, PO BOX 1495, Spokane, WA 99210, United States.
Exp Cell Res. 2017 Jun 15;355(2):95-104. doi: 10.1016/j.yexcr.2017.03.058. Epub 2017 Mar 31.
Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNA recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells.
维持功能性端粒对细胞的长期增殖至关重要。约15%的癌细胞端粒酶呈阴性，并激活端粒替代延长（ALT）途径来维持其端粒。最近的研究表明，人类CTC1/STN1/TEN1复合物（CST）在表达端粒酶的癌细胞的端粒维持中发挥多方面作用。然而，CST在ALT细胞端粒维持中的作用尚不清楚。在此，我们报告人类CST在整个细胞周期中形成一种功能性复合物，定位于ALT细胞中与ALT相关的早幼粒细胞白血病小体（APB）。抑制CST会诱导端粒不稳定，包括端粒脆性，并提高端粒DNA重组，导致端粒功能障碍。此外，CST缺陷显著减少了被称为C环和t环的染色体外环状端粒DNA的丰度。抑制CST还会导致ALT细胞多核化并损害细胞增殖。我们的研究结果表明，CST复合物在调节ALT细胞的端粒维持中起重要作用。
