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ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage

Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 l...

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Autores principales: Nowsheen, Somaira, Aziz, Khaled, Luo, Kuntian, Deng, Min, Qin, Bo, Yuan, Jian, Jeganathan, Karthik B., Yu, Jia, Zhang, Henan, Ding, Wei, van Deursen, Jan M., Lou, Zhenkun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048040/
https://www.ncbi.nlm.nih.gov/pubmed/30013081
http://dx.doi.org/10.1038/s41467-018-05161-0
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author Nowsheen, Somaira
Aziz, Khaled
Luo, Kuntian
Deng, Min
Qin, Bo
Yuan, Jian
Jeganathan, Karthik B.
Yu, Jia
Zhang, Henan
Ding, Wei
van Deursen, Jan M.
Lou, Zhenkun
author_facet Nowsheen, Somaira
Aziz, Khaled
Luo, Kuntian
Deng, Min
Qin, Bo
Yuan, Jian
Jeganathan, Karthik B.
Yu, Jia
Zhang, Henan
Ding, Wei
van Deursen, Jan M.
Lou, Zhenkun
author_sort Nowsheen, Somaira
collection PubMed
description Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506, in turn, recruits the protein phosphatase EYA, resulting in dephosphorylation of H2AX at Y142, which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus, ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation, offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together, these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity.
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spelling pubmed-60480402018-07-18 ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage Nowsheen, Somaira Aziz, Khaled Luo, Kuntian Deng, Min Qin, Bo Yuan, Jian Jeganathan, Karthik B. Yu, Jia Zhang, Henan Ding, Wei van Deursen, Jan M. Lou, Zhenkun Nat Commun Article Cells respond to cytotoxic DNA double-strand breaks by recruiting repair proteins to the damaged site. Phosphorylation of the histone variant H2AX at S139 and Y142 modulate its interaction with downstream DNA repair proteins and their recruitment to DNA lesions. Here we report ATM-dependent ZNF506 localization to the lesion through MDC1 following DNA damage. ZNF506, in turn, recruits the protein phosphatase EYA, resulting in dephosphorylation of H2AX at Y142, which further facilitates the recruitment of MDC1 and other downstream repair factors. Thus, ZNF506 regulates the early dynamic signaling in the DNA damage response (DDR) pathway and controls progressive downstream signal amplification. Cells lacking ZNF506 or harboring mutations found in cancer patient samples are more sensitive to radiation, offering a potential new therapeutic option for cancers with mutations in this pathway. Taken together, these results demonstrate how the DDR pathway is orchestrated by ZNF506 to maintain genomic integrity. Nature Publishing Group UK 2018-07-16 /pmc/articles/PMC6048040/ /pubmed/30013081 http://dx.doi.org/10.1038/s41467-018-05161-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nowsheen, Somaira
Aziz, Khaled
Luo, Kuntian
Deng, Min
Qin, Bo
Yuan, Jian
Jeganathan, Karthik B.
Yu, Jia
Zhang, Henan
Ding, Wei
van Deursen, Jan M.
Lou, Zhenkun
ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title_full ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title_fullStr ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title_full_unstemmed ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title_short ZNF506-dependent positive feedback loop regulates H2AX signaling after DNA damage
title_sort znf506-dependent positive feedback loop regulates h2ax signaling after dna damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048040/
https://www.ncbi.nlm.nih.gov/pubmed/30013081
http://dx.doi.org/10.1038/s41467-018-05161-0
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