Kang Shuangshuang, Cao Jiaojiao, Zhang Meiling, Li Xiaoya, Guo Qian-Liang, Zeng Huang, Wei Zuzhuang, Gong Xue, Wang Jing, Liu Bobo, Shu Bing, Xu Xiaoli, Huang Zhi-Shu, Li Ding
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Guangzhou and P.R. China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou and P.R. China.
RNA Biol. 2021 Dec;18(12):2261-2277. doi: 10.1080/15476286.2021.1899652. Epub 2021 Mar 22.
Telomere is a specialized DNA-protein complex that plays an important role in maintaining chromosomal integrity. Shelterin is a protein complex formed by six different proteins, with telomeric repeat factors 1 (TRF1) and 2 (TRF2) binding to double-strand telomeric DNA. Telomeric DNA consists of complementary G-rich and C-rich repeats, which could form G-quadruplex and intercalated motif (i-motif), respectively, during cell cycle. Its G-rich transcription product, telomeric repeat-containing RNA (TERRA), is essential for telomere stability and heterochromatin formation. After extensive screening, we found that acridine derivative and acridine dimer could selectively interact with TRF1 and telomeric i-motif, respectively. Compound blocked the binding of TRF1 with telomeric duplex DNA, resulting in up-regulation of TERRA. Accumulated TERRA could bind with TRF1 at its allosteric site and further destabilize its binding with telomeric DNA. In contrast, could destabilize telomeric i-motif, resulting in down-regulation of TERRA. Both compounds exhibited anti-tumour activity for A549 cells, but induced different DNA damage pathways. Compound significantly suppressed tumour growth in A549 xenograft mouse model. The function of telomeric i-motif structure was first studied with a selective binding ligand, which could play an important role in regulating TERRA transcription. Our results showed that appropriate level of TERRA transcript could be important for stability of telomere, and acridine derivatives could be further developed as anti-cancer agents targeting telomere. This research increased understanding for biological roles of telomeric i-motif, TRF1 and TERRA, as potential anti-cancer drug targets.
端粒是一种特殊的DNA - 蛋白质复合物，在维持染色体完整性方面发挥着重要作用。端粒保护蛋白复合体是由六种不同蛋白质形成的蛋白复合体，其中端粒重复因子1（TRF1）和2（TRF2）与双链端粒DNA结合。端粒DNA由富含G和富含C的互补重复序列组成，在细胞周期中它们可分别形成G - 四链体和插入基序（i - 基序）。其富含G的转录产物，即含端粒重复序列的RNA（TERRA），对于端粒稳定性和异染色质形成至关重要。经过广泛筛选，我们发现吖啶衍生物和吖啶二聚体可分别与TRF1和端粒i - 基序选择性相互作用。化合物阻断了TRF1与端粒双链DNA的结合，导致TERRA上调。积累的TERRA可在其别构位点与TRF1结合，并进一步破坏其与端粒DNA的结合。相比之下，可破坏端粒i - 基序，导致TERRA下调。两种化合物对A549细胞均表现出抗肿瘤活性，但诱导了不同的DNA损伤途径。化合物在A549异种移植小鼠模型中显著抑制肿瘤生长。首次使用选择性结合配体研究了端粒i - 基序结构的功能，其在调节TERRA转录中可能发挥重要作用。我们的结果表明，适当水平的TERRA转录本对于端粒稳定性可能很重要，并且吖啶衍生物可进一步开发为靶向端粒的抗癌药物。这项研究增进了对端粒i - 基序、TRF1和TERRA作为潜在抗癌药物靶点的生物学作用的理解。
