Transcriptional regulation of telomeric repeat-containing RNA by acridine derivatives. Issue 12 (2nd December 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: RNA biology. Volume 18:Issue 12(2021)
• Page Start: 2261
• Page End: 2277
• Publication Date: 2021-12-02
• Subjects: TERRA -- acridine -- TRF1 -- i-motif -- telomere -- cancer; RNA -- Periodicals; Molecular biology -- Periodicals; Molecular biology; RNA; Periodicals; 572.8805
• DOI: 10.1080/15476286.2021.1899652
• Languages: English
• ISSNs: 1547-6286

Abstract

ABSTRACT: 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 2c and acridine dimer DI26 could selectively interact with TRF1 and telomeric i-motif, respectively. Compound 2c 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, DI26 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 2c 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.