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

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.

• Authors: Cristina Espinosa-Diez, RaeAnna Wilson, Namita Chatterjee, Clayton Hudson, Rebecca Ruhl, Christina Hipfinger, Erin Helms, Omar F Khan, Daniel G Anderson, Sudarshan Anand
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 6 Pg. 632 (05 24 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29795397 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intercellular Signaling Peptides and Proteins
• MicroRNAs
• Multiprotein Complexes

Topics

• Animals
• Cellular Senescence (genetics, radiation effects)
• DNA Damage (genetics)
• DNA Repair (genetics, radiation effects)
• Female
• Gene Expression Regulation (radiation effects)
• Human Umbilical Vein Endothelial Cells (metabolism, radiation effects)
• Humans
• Intercellular Signaling Peptides and Proteins (metabolism)
• Mice, Nude
• MicroRNAs (genetics, metabolism)
• Multiprotein Complexes (metabolism)
• Neovascularization, Physiologic (genetics, radiation effects)
• Radiation, Ionizing