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The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted

A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long...

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Detalles Bibliográficos
Autores principales: Silva, Bruno, Arora, Rajika, Azzalin, Claus M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522348/
https://www.ncbi.nlm.nih.gov/pubmed/36122232
http://dx.doi.org/10.1073/pnas.2208669119
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author Silva, Bruno
Arora, Rajika
Azzalin, Claus M.
author_facet Silva, Bruno
Arora, Rajika
Azzalin, Claus M.
author_sort Silva, Bruno
collection PubMed
description A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy.
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spelling pubmed-95223482022-09-30 The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted Silva, Bruno Arora, Rajika Azzalin, Claus M. Proc Natl Acad Sci U S A Biological Sciences A substantial number of human cancers are telomerase-negative and elongate physiologically damaged telomeres through a break-induced replication (BIR)-based mechanism known as alternative lengthening of telomeres (ALT). We recently demonstrated that inhibiting the transcription of the telomeric long noncoding RNA TERRA suppresses telomere damage and ALT features, indicating that telomere transcription is a main trigger of ALT activity. Here we show that experimentally increased TERRA transcription not only increases ALT features, as expected, but also causes rapid loss of telomeric DNA through a pathway that requires the endonuclease Mus81. Our data indicate that the ALT mechanism can endanger telomere integrity if not properly controlled and point to TERRA transcription as a uniquely versatile target for therapy. National Academy of Sciences 2022-09-19 2022-09-27 /pmc/articles/PMC9522348/ /pubmed/36122232 http://dx.doi.org/10.1073/pnas.2208669119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Biological Sciences
Silva, Bruno
Arora, Rajika
Azzalin, Claus M.
The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title_full The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title_fullStr The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title_full_unstemmed The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title_short The alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
title_sort alternative lengthening of telomeres mechanism jeopardizes telomere integrity if not properly restricted
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9522348/
https://www.ncbi.nlm.nih.gov/pubmed/36122232
http://dx.doi.org/10.1073/pnas.2208669119
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