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Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway

Faithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Herein, we report that...

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Autores principales: Su, Fengtao, Bhattacharya, Souparno, Abdisalaam, Salim, Mukherjee, Shibani, Yajima, Hirohiko, Yang, Yanyong, Mishra, Ritu, Srinivasan, Kalayarasan, Ghose, Subroto, Chen, David J., Yannone, Steven M., Asaithamby, Aroumougame
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807982/
https://www.ncbi.nlm.nih.gov/pubmed/26695548
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author Su, Fengtao
Bhattacharya, Souparno
Abdisalaam, Salim
Mukherjee, Shibani
Yajima, Hirohiko
Yang, Yanyong
Mishra, Ritu
Srinivasan, Kalayarasan
Ghose, Subroto
Chen, David J.
Yannone, Steven M.
Asaithamby, Aroumougame
author_facet Su, Fengtao
Bhattacharya, Souparno
Abdisalaam, Salim
Mukherjee, Shibani
Yajima, Hirohiko
Yang, Yanyong
Mishra, Ritu
Srinivasan, Kalayarasan
Ghose, Subroto
Chen, David J.
Yannone, Steven M.
Asaithamby, Aroumougame
author_sort Su, Fengtao
collection PubMed
description Faithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Herein, we report that ATR-mediated WRN phosphorylation is needed for DNA replication and repair upon replication stress. A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. The dynamic interaction between WRN and DNA is required for the suppression of new origin firing and Rad51-dependent double-stranded DNA break repair. Significantly, ATR-mediated WRN phosphorylation is critical for the suppression of chromosome breakage during replication stress. These findings reveal a unique role for WRN as a modulator of DNA repair, replication, and recombination, and link ATR-WRN signaling to the maintenance of genome stability.
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spelling pubmed-48079822016-04-19 Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway Su, Fengtao Bhattacharya, Souparno Abdisalaam, Salim Mukherjee, Shibani Yajima, Hirohiko Yang, Yanyong Mishra, Ritu Srinivasan, Kalayarasan Ghose, Subroto Chen, David J. Yannone, Steven M. Asaithamby, Aroumougame Oncotarget Research Paper: Gerotarget (Focus on Aging) Faithful and complete genome replication in human cells is essential for preventing the accumulation of cancer-promoting mutations. WRN, the protein defective in Werner syndrome, plays critical roles in preventing replication stress, chromosome instability, and tumorigenesis. Herein, we report that ATR-mediated WRN phosphorylation is needed for DNA replication and repair upon replication stress. A serine residue, S1141, in WRN is phosphorylated in vivo by the ATR kinase in response to replication stress. ATR-mediated WRN S1141 phosphorylation leads to ubiquitination of WRN, facilitating the reversible interaction of WRN with perturbed replication forks and subsequent degradation of WRN. The dynamic interaction between WRN and DNA is required for the suppression of new origin firing and Rad51-dependent double-stranded DNA break repair. Significantly, ATR-mediated WRN phosphorylation is critical for the suppression of chromosome breakage during replication stress. These findings reveal a unique role for WRN as a modulator of DNA repair, replication, and recombination, and link ATR-WRN signaling to the maintenance of genome stability. Impact Journals LLC 2015-12-18 /pmc/articles/PMC4807982/ /pubmed/26695548 Text en Copyright: © 2016 Su et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper: Gerotarget (Focus on Aging)
Su, Fengtao
Bhattacharya, Souparno
Abdisalaam, Salim
Mukherjee, Shibani
Yajima, Hirohiko
Yang, Yanyong
Mishra, Ritu
Srinivasan, Kalayarasan
Ghose, Subroto
Chen, David J.
Yannone, Steven M.
Asaithamby, Aroumougame
Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title_full Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title_fullStr Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title_full_unstemmed Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title_short Replication stress induced site-specific phosphorylation targets WRN to the ubiquitin-proteasome pathway
title_sort replication stress induced site-specific phosphorylation targets wrn to the ubiquitin-proteasome pathway
topic Research Paper: Gerotarget (Focus on Aging)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807982/
https://www.ncbi.nlm.nih.gov/pubmed/26695548
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