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CDK1 phosphorylates WRN at collapsed replication forks
Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates i...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028418/ https://www.ncbi.nlm.nih.gov/pubmed/27634057 http://dx.doi.org/10.1038/ncomms12880 |
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author | Palermo, Valentina Rinalducci, Sara Sanchez, Massimo Grillini, Francesca Sommers, Joshua A. Brosh, Robert M. Zolla, Lello Franchitto, Annapaola Pichierri, Pietro |
author_facet | Palermo, Valentina Rinalducci, Sara Sanchez, Massimo Grillini, Francesca Sommers, Joshua A. Brosh, Robert M. Zolla, Lello Franchitto, Annapaola Pichierri, Pietro |
author_sort | Palermo, Valentina |
collection | PubMed |
description | Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability. Mechanistically, S1133 phosphorylation of WRN is dispensable for relocalization in foci but is involved in the interaction with the MRE11 complex. Loss of WRN phosphorylation negatively affects MRE11 foci formation and acts in a dominant negative manner to prevent long-range resection altogether, thereby licensing NHEJ at collapsed forks. Collectively, we unveil a CDK1-dependent regulation of the WRN-DNA2-mediated resection and identify an undescribed function of WRN as a DSB repair pathway switch. |
format | Online Article Text |
id | pubmed-5028418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50284182016-09-26 CDK1 phosphorylates WRN at collapsed replication forks Palermo, Valentina Rinalducci, Sara Sanchez, Massimo Grillini, Francesca Sommers, Joshua A. Brosh, Robert M. Zolla, Lello Franchitto, Annapaola Pichierri, Pietro Nat Commun Article Regulation of end-processing is critical for accurate repair and to switch between homologous recombination (HR) and non-homologous end joining (NHEJ). End resection is a two-stage process but very little is known about regulation of the long-range resection, especially in humans. WRN participates in one of the two alternative long-range resection pathways mediated by DNA2 or EXO1. Here we demonstrate that phosphorylation of WRN by CDK1 is essential to perform DNA2-dependent end resection at replication-related DSBs, promoting HR, replication recovery and chromosome stability. Mechanistically, S1133 phosphorylation of WRN is dispensable for relocalization in foci but is involved in the interaction with the MRE11 complex. Loss of WRN phosphorylation negatively affects MRE11 foci formation and acts in a dominant negative manner to prevent long-range resection altogether, thereby licensing NHEJ at collapsed forks. Collectively, we unveil a CDK1-dependent regulation of the WRN-DNA2-mediated resection and identify an undescribed function of WRN as a DSB repair pathway switch. Nature Publishing Group 2016-09-16 /pmc/articles/PMC5028418/ /pubmed/27634057 http://dx.doi.org/10.1038/ncomms12880 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Palermo, Valentina Rinalducci, Sara Sanchez, Massimo Grillini, Francesca Sommers, Joshua A. Brosh, Robert M. Zolla, Lello Franchitto, Annapaola Pichierri, Pietro CDK1 phosphorylates WRN at collapsed replication forks |
title | CDK1 phosphorylates WRN at collapsed replication forks |
title_full | CDK1 phosphorylates WRN at collapsed replication forks |
title_fullStr | CDK1 phosphorylates WRN at collapsed replication forks |
title_full_unstemmed | CDK1 phosphorylates WRN at collapsed replication forks |
title_short | CDK1 phosphorylates WRN at collapsed replication forks |
title_sort | cdk1 phosphorylates wrn at collapsed replication forks |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028418/ https://www.ncbi.nlm.nih.gov/pubmed/27634057 http://dx.doi.org/10.1038/ncomms12880 |
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