التفاصيل البيبلوغرافية
| العنوان: |
ATM–Dependent MiR-335 Targets CtIP and Modulates the DNA Damage Response |
| المؤلفون: |
Martin, Nathan T., Nakamura, Kotoka, Davies, Robert, Nahas, Shareef A., Brown, Christina, Tunuguntla, Rashmi, Gatti, Richard A., Hu, Hailiang |
| المصدر: |
PLoS Genetics; May2013, Vol. 9 Issue 5, p1-10, 10p |
| مصطلحات موضوعية: |
DNA damage, BIOCHEMICAL genetics, MICRORNA genetics, IRRADIATION, CELL lines |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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