MOE Key Laboratory of Gene Function and Regulation, Guangzhou Key Laboratory of Healthy Aging Research and SYSU-BCM Joint Research Center, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Nucleic Acids Res. 2020 Jun 19;48(11):6019-6031. doi: 10.1093/nar/gkaa224.
ALT tumor cells often contain abundant DNA damage foci at telomeres and rely on the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. How the telomere chromatin is regulated and maintained in these cells remains largely unknown. In this study, we present evidence that heterochromatin protein 1 binding protein 3 (HP1BP3) can localize to telomeres and is particularly enriched on telomeres in ALT cells. HP1BP3 inhibition led to preferential growth inhibition of ALT cells, which was accompanied by telomere chromatin decompaction, increased presence of C-circles, more pronounced ALT-associated phenotypes and elongated telomeres. Furthermore, HP1BP3 appeared to participate in regulating telomere histone H3K9me3 epigenetic marks. Taken together, our data suggest that HP1BP3 functions on telomeres to maintain telomere chromatin and represents a novel target for inhibiting ALT cancer cells.
ALT 肿瘤细胞在端粒处通常含有丰富的 DNA 损伤焦点，并依赖端粒的非经典延长（ALT）机制来维持其端粒。这些细胞中端粒染色质如何被调控和维持在很大程度上仍是未知的。在这项研究中，我们提供了证据表明异染色质蛋白 1 结合蛋白 3（HP1BP3）可以定位于端粒，并且在 ALT 细胞中端粒上特别丰富。抑制 HP1BP3 导致 ALT 细胞优先受到抑制，这伴随着端粒染色质解压缩、更多的 C-环出现、更明显的 ALT 相关表型和端粒延长。此外，HP1BP3 似乎参与调节端粒组蛋白 H3K9me3 表观遗传标记。总之，我们的数据表明，HP1BP3 在端粒上发挥作用以维持端粒染色质，并代表了抑制 ALT 癌细胞的一个新靶点。
