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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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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. |
format | Online Article Text |
id | pubmed-9522348 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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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