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121975 |
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|a Espinosa-Diez, Cristina
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|a Massachusetts Institute of Technology. Department of Chemical Engineering
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|a Massachusetts Institute of Technology. Institute for Medical Engineering & Science
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|a Harvard University-
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|a Koch Institute for Integrative Cancer Research at MIT
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|a Wilson, RaeAnna
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|a Chatterjee, Namita
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|a Hudson, Clayton
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|a Ruhl, Rebecca
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|a Hipfinger, Christina
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|a Helms, Erin
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|a Khan, Omar Fizal
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|a Anderson, Daniel Griffith
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|a Anand, Sudarshan
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|a MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling
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|b Springer Science and Business Media LLC,
|c 2019-08-09T16:03:30Z.
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|z Get fulltext
|u https://hdl.handle.net/1721.1/121975
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|a MicroRNAs (miRs) contribute to biological robustness by buffering cellular processes from external perturbations. Here we report an unexpected link between DNA damage response and angiogenic signaling that is buffered by a miR. We demonstrate that genotoxic stress-induced miR-494 inhibits the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Gain-and loss-of-function experiments show that miR-494 exacerbates DNA damage and drives endothelial senescence. Increase of miR-494 affects telomerase activity, activates p21, decreases pRb pathways, and diminishes angiogenic sprouting. Genetic and pharmacological disruption of the MRN pathway decreases VEGF signaling, phenocopies miR-494-induced senescence, and disrupts angiogenic sprouting. Vascular-Targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Our work identifies a putative miR-facilitated mechanism by which endothelial cells can be insulated against VEGF signaling to facilitate the onset of senescence and highlight the potential of targeting DNA repair to disrupt pathological angiogenesis.
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|a en
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|a Article
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|t Cell Death & Disease
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