Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Institute for Molecular Health Sciences, ETHZ, Zürich, Switzerland.
Nat Commun. 2021 Jun 18;12(1):3760. doi: 10.1038/s41467-021-24097-6.
Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.
端粒的替代性延长（ALT）是一种基于断裂诱导复制（BIR）的机制，可在人类癌细胞的一部分中延长端粒。虽然在启动 ALT 时需要在端粒处发生自发的 DNA 损伤的观点，但这种生理端粒不稳定性的分子触发因素在很大程度上尚不清楚。我们之前提出，端粒的长非编码 RNA TERRA 可能代表这样的触发因素之一；然而，由于缺乏在细胞中抑制 TERRA 转录的工具，我们的假设仍然是推测性的。我们已经开发了转录激活样效应物（Transcription Activator-Like Effectors），能够在 ALT 细胞系中从多个染色体末端快速抑制 TERRA 转录。TERRA 转录抑制降低了端粒处的 DNA 复制应激和 DNA 损伤的标记，并损害了 ALT 活性和端粒长度的维持。我们得出的结论是，TERRA 转录在 ALT 细胞中端粒完整性的不稳定性，从而触发 BIR 并促进端粒延长。我们的数据表明，TERRA 转录的操纵可能是一种有前途的治疗靶点。
