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Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function

53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage...

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Autores principales: Byrum, Andrea K., Carvajal-Maldonado, Denisse, Mudge, Miranda C., Valle-Garcia, David, Majid, Mona C., Patel, Romil, Sowa, Mathew E., Gygi, Steven P., Harper, J. Wade, Shi, Yang, Vindigni, Alessandro, Mosammaparast, Nima
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363440/
https://www.ncbi.nlm.nih.gov/pubmed/30602538
http://dx.doi.org/10.1083/jcb.201803003
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author Byrum, Andrea K.
Carvajal-Maldonado, Denisse
Mudge, Miranda C.
Valle-Garcia, David
Majid, Mona C.
Patel, Romil
Sowa, Mathew E.
Gygi, Steven P.
Harper, J. Wade
Shi, Yang
Vindigni, Alessandro
Mosammaparast, Nima
author_facet Byrum, Andrea K.
Carvajal-Maldonado, Denisse
Mudge, Miranda C.
Valle-Garcia, David
Majid, Mona C.
Patel, Romil
Sowa, Mathew E.
Gygi, Steven P.
Harper, J. Wade
Shi, Yang
Vindigni, Alessandro
Mosammaparast, Nima
author_sort Byrum, Andrea K.
collection PubMed
description 53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability.
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spelling pubmed-63634402019-08-04 Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function Byrum, Andrea K. Carvajal-Maldonado, Denisse Mudge, Miranda C. Valle-Garcia, David Majid, Mona C. Patel, Romil Sowa, Mathew E. Gygi, Steven P. Harper, J. Wade Shi, Yang Vindigni, Alessandro Mosammaparast, Nima J Cell Biol Research Articles 53BP1 is a chromatin-associated protein that regulates the DNA damage response. In this study, we identify the TPX2/Aurora A heterodimer, nominally considered a mitotic kinase complex, as a novel binding partner of 53BP1. We find that TPX2/Aurora A plays a previously unrecognized role in DNA damage repair and replication fork stability by counteracting 53BP1 function. Loss of TPX2 or Aurora A compromises DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, loss of TPX2 or Aurora A causes deprotection of stalled replication forks upon replication stress induction. This fork protection pathway counteracts MRE11 nuclease activity but functions in parallel to BRCA1. Strikingly, concurrent loss of 53BP1 rescues not only BRCA1/Rad51 recruitment but also the fork instability induced upon TPX2 loss. Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability. Rockefeller University Press 2019-02-04 /pmc/articles/PMC6363440/ /pubmed/30602538 http://dx.doi.org/10.1083/jcb.201803003 Text en © 2019 Byrum et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Byrum, Andrea K.
Carvajal-Maldonado, Denisse
Mudge, Miranda C.
Valle-Garcia, David
Majid, Mona C.
Patel, Romil
Sowa, Mathew E.
Gygi, Steven P.
Harper, J. Wade
Shi, Yang
Vindigni, Alessandro
Mosammaparast, Nima
Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title_full Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title_fullStr Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title_full_unstemmed Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title_short Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function
title_sort mitotic regulators tpx2 and aurora a protect dna forks during replication stress by counteracting 53bp1 function
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363440/
https://www.ncbi.nlm.nih.gov/pubmed/30602538
http://dx.doi.org/10.1083/jcb.201803003
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