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

Bruno Silva, Rajika Arora, Claus M. Azzalin
doi: https://doi.org/10.1101/2021.02.18.431840
Bruno Silva
1Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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Rajika Arora
1Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
2Institute for Molecular Health Sciences, ETHZ, Zürich, Switzerland
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Claus M. Azzalin
1Instituto de Medicina Molecular João Lobo Antunes (iMM), Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
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  • For correspondence: cmazzalin@medicina.ulisboa.pt
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ABSTRACT

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 for ALT to occur, 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 now 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 initiating BIR and supporting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 18, 2021.
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TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Bruno Silva, Rajika Arora, Claus M. Azzalin
bioRxiv 2021.02.18.431840; doi: https://doi.org/10.1101/2021.02.18.431840
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TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Bruno Silva, Rajika Arora, Claus M. Azzalin
bioRxiv 2021.02.18.431840; doi: https://doi.org/10.1101/2021.02.18.431840

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