TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells

• DOI: 10.1038/s41467-021-24097-6
• Publication Date: 2021-06-18T10:03:33Z
• Authors: Bruno Silva; Rajika Arora; Silvia Bione; Claus M. Azzalin
• Keywords: Transcription; Chromosome instability

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in subset human cancer cells. While the notion that spontaneous DNA damage at required to initiate ALT, molecular triggers this physiological telomere instability are largely unknown. We previously proposed telomeric long noncoding RNA TERRA may represent one such trigger; however, given lack tools suppress transcription cells, our hypothesis remained speculative. have developed Transcription Activator-Like Effectors able rapidly inhibit from multiple chromosome ends an ALT cell line. inhibition decreases marks replication stress and impairs activity length maintenance. conclude actively destabilizes integrity thereby triggering BIR promoting elongation. Our data point manipulation as potentially useful target for therapy.