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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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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. |
format | Online Article Text |
id | pubmed-6048040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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