MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling
Name
s41419-018-0690-y.pdf
Description
Published version
Size
1.82 MB
Format
Adobe PDF
Checksum (MD5)
1ff57a21736ba516dbe30243638e1ede
Author(s)
Espinosa-Diez, Cristina
Wilson, RaeAnna
Chatterjee, Namita
Hudson, Clayton
Ruhl, Rebecca
Hipfinger, Christina
Helms, Erin
Khan, Omar Fizal
Anderson, Daniel Griffith
Anand, Sudarshan
Date Issued
May 2018
Journal
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Citation
Espinosa-Diez, Cristina et al. "MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling." Cell Death & Disease 9, 6 (May 2018): 632 © 2018 The Author(s)
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International license
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/s41419-018-0690-y
