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ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity

Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX de...

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Autores principales: Lovejoy, Courtney A., Takai, Kaori, Huh, Michael S., Picketts, David J., de Lange, Titia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959610/
https://www.ncbi.nlm.nih.gov/pubmed/31895940
http://dx.doi.org/10.1371/journal.pbio.3000594
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author Lovejoy, Courtney A.
Takai, Kaori
Huh, Michael S.
Picketts, David J.
de Lange, Titia
author_facet Lovejoy, Courtney A.
Takai, Kaori
Huh, Michael S.
Picketts, David J.
de Lange, Titia
author_sort Lovejoy, Courtney A.
collection PubMed
description Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway.
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spelling pubmed-69596102020-01-26 ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity Lovejoy, Courtney A. Takai, Kaori Huh, Michael S. Picketts, David J. de Lange, Titia PLoS Biol Research Article Alpha thalassemia/mental retardation syndrome X-linked chromatin remodeler (ATRX), a DAXX (death domain-associated protein) interacting protein, is often lost in cells using the alternative lengthening of telomeres (ALT) pathway, but it is not known how ATRX loss leads to ALT. We report that ATRX deletion from mouse cells altered the repair of telomeric double-strand breaks (DSBs) and induced ALT-like phenotypes, including ALT-associated promyelocytic leukemia (PML) bodies (APBs), telomere sister chromatid exchanges (T-SCEs), and extrachromosomal telomeric signals (ECTSs). Mechanistically, we show that ATRX affects telomeric DSB repair by promoting cohesion of sister telomeres and that loss of ATRX in ALT cells results in diminished telomere cohesion. In addition, we document a role for DAXX in the repair of telomeric DSBs. Removal of telomeric cohesion in combination with DAXX deficiency recapitulates all telomeric DSB repair phenotypes associated with ATRX loss. The data reveal that ATRX has an effect on telomeric DSB repair and that this role involves both telomere cohesion and a DAXX-dependent pathway. Public Library of Science 2020-01-02 /pmc/articles/PMC6959610/ /pubmed/31895940 http://dx.doi.org/10.1371/journal.pbio.3000594 Text en © 2020 Lovejoy et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lovejoy, Courtney A.
Takai, Kaori
Huh, Michael S.
Picketts, David J.
de Lange, Titia
ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title_full ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title_fullStr ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title_full_unstemmed ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title_short ATRX affects the repair of telomeric DSBs by promoting cohesion and a DAXX-dependent activity
title_sort atrx affects the repair of telomeric dsbs by promoting cohesion and a daxx-dependent activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959610/
https://www.ncbi.nlm.nih.gov/pubmed/31895940
http://dx.doi.org/10.1371/journal.pbio.3000594
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