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PLoS Genet. 2013 May;9(5):e1003505. doi: 10.1371/journal.pgen.1003505. Epub 2013 May 16.

ATM-dependent MiR-335 targets CtIP and modulates the DNA damage response.

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Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA.


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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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