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RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening
Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362809/ https://www.ncbi.nlm.nih.gov/pubmed/30692206 http://dx.doi.org/10.1101/gad.319723.118 |
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author | Verma, Priyanka Dilley, Robert L. Zhang, Tianpeng Gyparaki, Melina T. Li, Yiwen Greenberg, Roger A. |
author_facet | Verma, Priyanka Dilley, Robert L. Zhang, Tianpeng Gyparaki, Melina T. Li, Yiwen Greenberg, Roger A. |
author_sort | Verma, Priyanka |
collection | PubMed |
description | Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52-null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability. |
format | Online Article Text |
id | pubmed-6362809 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-63628092019-08-01 RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening Verma, Priyanka Dilley, Robert L. Zhang, Tianpeng Gyparaki, Melina T. Li, Yiwen Greenberg, Roger A. Genes Dev Research Paper Approximately 15% of cancers use homologous recombination for alternative lengthening of telomeres (ALT). How the initiating genomic lesions invoke homology-directed telomere synthesis remains enigmatic. Here, we show that distinct dependencies exist for telomere synthesis in response to replication stress or DNA double-strand breaks (DSBs). RAD52 deficiency reduced spontaneous telomeric DNA synthesis and replication stress-associated recombination in G2, concomitant with telomere shortening and damage. However, viability and proliferation remained unaffected, suggesting that alternative telomere recombination mechanisms compensate in the absence of RAD52. In agreement, RAD52 was dispensable for DSB-induced telomere synthesis. Moreover, a targeted CRISPR screen revealed that loss of the structure-specific endonuclease scaffold SLX4 reduced the proliferation of RAD52-null ALT cells. While SLX4 was dispensable for RAD52-mediated ALT telomere synthesis in G2, combined SLX4 and RAD52 loss resulted in elevated telomere loss, unresolved telomere recombination intermediates, and mitotic infidelity. These findings establish that RAD52 and SLX4 mediate distinct postreplicative DNA repair processes that maintain ALT telomere stability and cancer cell viability. Cold Spring Harbor Laboratory Press 2019-02-01 /pmc/articles/PMC6362809/ /pubmed/30692206 http://dx.doi.org/10.1101/gad.319723.118 Text en © 2019 Verma et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Verma, Priyanka Dilley, Robert L. Zhang, Tianpeng Gyparaki, Melina T. Li, Yiwen Greenberg, Roger A. RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title | RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title_full | RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title_fullStr | RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title_full_unstemmed | RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title_short | RAD52 and SLX4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
title_sort | rad52 and slx4 act nonepistatically to ensure telomere stability during alternative telomere lengthening |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362809/ https://www.ncbi.nlm.nih.gov/pubmed/30692206 http://dx.doi.org/10.1101/gad.319723.118 |
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