MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling article

Cristina Espinosa-Diez, Raeanna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F. Khan, Daniel G. Anderson, Sudarshan Anand

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number632
JournalCell Death and Disease
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Espinosa-Diez, C., Wilson, R., Chatterjee, N., Hudson, C., Ruhl, R., Hipfinger, C., Helms, E., Khan, O. F., Anderson, D. G., & Anand, S. (2018). MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling article. Cell Death and Disease, 9(6), [632]. https://doi.org/10.1038/s41419-018-0690-y