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MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts

Repair of DNA double-strand breaks (DSBs) with complex ends poses a special challenge, as additional processing is required before DNA ligation. For example, protein–DNA adducts must be removed to allow repair by either nonhomologous end joining or homology-directed repair. Here, we investigated the...

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Detalles Bibliográficos
Autores principales: Aparicio, Tomas, Baer, Richard, Gottesman, Max, Gautier, Jean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754713/
https://www.ncbi.nlm.nih.gov/pubmed/26880199
http://dx.doi.org/10.1083/jcb.201504005
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author Aparicio, Tomas
Baer, Richard
Gottesman, Max
Gautier, Jean
author_facet Aparicio, Tomas
Baer, Richard
Gottesman, Max
Gautier, Jean
author_sort Aparicio, Tomas
collection PubMed
description Repair of DNA double-strand breaks (DSBs) with complex ends poses a special challenge, as additional processing is required before DNA ligation. For example, protein–DNA adducts must be removed to allow repair by either nonhomologous end joining or homology-directed repair. Here, we investigated the processing of topoisomerase II (Top2)–DNA adducts induced by treatment with the chemotherapeutic agent etoposide. Through biochemical analysis in Xenopus laevis egg extracts, we establish that the MRN (Mre11, Rad50, and Nbs1) complex, CtIP, and BRCA1 are required for both the removal of Top2–DNA adducts and the subsequent resection of Top2-adducted DSB ends. Moreover, the interaction between CtIP and BRCA1, although dispensable for resection of endonuclease-generated DSB ends, is required for resection of Top2-adducted DSBs, as well as for cellular resistance to etoposide during genomic DNA replication.
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spelling pubmed-47547132016-08-15 MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts Aparicio, Tomas Baer, Richard Gottesman, Max Gautier, Jean J Cell Biol Research Articles Repair of DNA double-strand breaks (DSBs) with complex ends poses a special challenge, as additional processing is required before DNA ligation. For example, protein–DNA adducts must be removed to allow repair by either nonhomologous end joining or homology-directed repair. Here, we investigated the processing of topoisomerase II (Top2)–DNA adducts induced by treatment with the chemotherapeutic agent etoposide. Through biochemical analysis in Xenopus laevis egg extracts, we establish that the MRN (Mre11, Rad50, and Nbs1) complex, CtIP, and BRCA1 are required for both the removal of Top2–DNA adducts and the subsequent resection of Top2-adducted DSB ends. Moreover, the interaction between CtIP and BRCA1, although dispensable for resection of endonuclease-generated DSB ends, is required for resection of Top2-adducted DSBs, as well as for cellular resistance to etoposide during genomic DNA replication. The Rockefeller University Press 2016-02-15 /pmc/articles/PMC4754713/ /pubmed/26880199 http://dx.doi.org/10.1083/jcb.201504005 Text en © 2016 Aparicio et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Aparicio, Tomas
Baer, Richard
Gottesman, Max
Gautier, Jean
MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title_full MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title_fullStr MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title_full_unstemmed MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title_short MRN, CtIP, and BRCA1 mediate repair of topoisomerase II–DNA adducts
title_sort mrn, ctip, and brca1 mediate repair of topoisomerase ii–dna adducts
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754713/
https://www.ncbi.nlm.nih.gov/pubmed/26880199
http://dx.doi.org/10.1083/jcb.201504005
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