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,...
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2013
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oai:doaj.org-article:c7fe259b589c45e58d38359a434aec1a2021-11-18T06:19:38ZATM-dependent MiR-335 targets CtIP and modulates the DNA damage response.1553-73901553-740410.1371/journal.pgen.1003505https://doaj.org/article/c7fe259b589c45e58d38359a434aec1a2013-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23696749/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404ATM 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.Nathan T MartinKotoka NakamuraRobert DaviesShareef A NahasChristina BrownRashmi TunuguntlaRichard A GattiHailiang HuPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 9, Iss 5, p e1003505 (2013) |
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DOAJ |
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DOAJ |
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EN |
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Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 Nathan T Martin Kotoka Nakamura Robert Davies Shareef A Nahas Christina Brown Rashmi Tunuguntla Richard A Gatti Hailiang Hu ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response. |
| 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 |
article |
| author |
Nathan T Martin Kotoka Nakamura Robert Davies Shareef A Nahas Christina Brown Rashmi Tunuguntla Richard A Gatti Hailiang Hu |
| author_facet |
Nathan T Martin Kotoka Nakamura Robert Davies Shareef A Nahas Christina Brown Rashmi Tunuguntla Richard A Gatti Hailiang Hu |
| author_sort |
Nathan T Martin |
| title |
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_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_sort |
atm-dependent mir-335 targets ctip and modulates the dna damage response. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/c7fe259b589c45e58d38359a434aec1a |
| work_keys_str_mv |
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