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ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response
ATM plays a critical role in cellular responses to DNA double-strand breaks (DSBs). We describe a new ATM–mediated DSB–induced DNA damage response pathway involving microRNA (miRNA): irradiation (IR)-induced DSBs activate ATM, which leads to the downregulation of miR-335, a miRNA that targets CtIP,...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656122/ https://www.ncbi.nlm.nih.gov/pubmed/23696749 http://dx.doi.org/10.1371/journal.pgen.1003505 |
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author | Martin, Nathan T. Nakamura, Kotoka Davies, Robert Nahas, Shareef A. Brown, Christina Tunuguntla, Rashmi Gatti, Richard A. Hu, Hailiang |
author_facet | Martin, Nathan T. Nakamura, Kotoka Davies, Robert Nahas, Shareef A. Brown, Christina Tunuguntla, Rashmi Gatti, Richard A. Hu, Hailiang |
author_sort | Martin, Nathan T. |
collection | PubMed |
description | ATM plays a critical role in cellular responses to DNA double-strand breaks (DSBs). We describe a new ATM–mediated DSB–induced DNA damage response pathway involving microRNA (miRNA): irradiation (IR)-induced DSBs activate ATM, which leads to the downregulation of miR-335, a miRNA that targets CtIP, which is an important trigger of DNA end resection in homologous recombination repair (HRR). We demonstrate that CREB is responsible for a large portion of miR-335 expression by binding to the promoter region of miR-335. CREB binding is greatly reduced after IR, corroborating with previous studies that IR-activated ATM phosphorylates CREB to reduce its transcription activity. Overexpression of miR-335 in HeLa cells resulted in reduced CtIP levels and post-IR colony survival and BRCA1 foci formation. Further, in two patient-derived lymphoblastoid cell lines with decreased post-IR colony survival, a “radiosensitive” phenotype, we demonstrated elevated miR-335 expression, reduced CtIP levels, and reduced BRCA1 foci formation. Colony survival, BRCA1 foci, and CtIP levels were partially rescued by miRNA antisense AMO-miR-335 treatment. Taken together, these findings strongly suggest that an ATM–dependent CREB–miR-335–CtIP axis influences the selection of HRR for repair of certain DSB lesions. |
format | Online Article Text |
id | pubmed-3656122 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36561222013-05-21 ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response Martin, Nathan T. Nakamura, Kotoka Davies, Robert Nahas, Shareef A. Brown, Christina Tunuguntla, Rashmi Gatti, Richard A. Hu, Hailiang PLoS Genet Research Article ATM plays a critical role in cellular responses to DNA double-strand breaks (DSBs). We describe a new ATM–mediated DSB–induced DNA damage response pathway involving microRNA (miRNA): irradiation (IR)-induced DSBs activate ATM, which leads to the downregulation of miR-335, a miRNA that targets CtIP, which is an important trigger of DNA end resection in homologous recombination repair (HRR). We demonstrate that CREB is responsible for a large portion of miR-335 expression by binding to the promoter region of miR-335. CREB binding is greatly reduced after IR, corroborating with previous studies that IR-activated ATM phosphorylates CREB to reduce its transcription activity. Overexpression of miR-335 in HeLa cells resulted in reduced CtIP levels and post-IR colony survival and BRCA1 foci formation. Further, in two patient-derived lymphoblastoid cell lines with decreased post-IR colony survival, a “radiosensitive” phenotype, we demonstrated elevated miR-335 expression, reduced CtIP levels, and reduced BRCA1 foci formation. Colony survival, BRCA1 foci, and CtIP levels were partially rescued by miRNA antisense AMO-miR-335 treatment. Taken together, these findings strongly suggest that an ATM–dependent CREB–miR-335–CtIP axis influences the selection of HRR for repair of certain DSB lesions. Public Library of Science 2013-05-16 /pmc/articles/PMC3656122/ /pubmed/23696749 http://dx.doi.org/10.1371/journal.pgen.1003505 Text en © 2013 Martin et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Martin, Nathan T. Nakamura, Kotoka Davies, Robert Nahas, Shareef A. Brown, Christina Tunuguntla, Rashmi Gatti, Richard A. Hu, Hailiang ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title | ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title_full | ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title_fullStr | ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title_full_unstemmed | ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title_short | ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
title_sort | atm–dependent mir-335 targets ctip and modulates the dna damage response |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3656122/ https://www.ncbi.nlm.nih.gov/pubmed/23696749 http://dx.doi.org/10.1371/journal.pgen.1003505 |
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