TY - JOUR
T1 - MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling article
AU - Espinosa-Diez, Cristina
AU - Wilson, Raeanna
AU - Chatterjee, Namita
AU - Hudson, Clayton
AU - Ruhl, Rebecca
AU - Hipfinger, Christina
AU - Helms, Erin
AU - Khan, Omar F.
AU - Anderson, Daniel G.
AU - Anand, Sudarshan
N1 - Funding Information:
We thank Lisa Coussens (OHSU) for help with the PyMT model and sharing archived FFPE tissue sections from ref. 47. We thank Sergio Fazio and Stephen Lloyd (OHSU) for useful discussions. We thank Shushan Rana and Katherine Kelly (OHSU) for comments on the manuscript. We acknowledge the OHSU Advanced Light Microscopy Core, Knight Cancer Institute Flow Cytometry Core, and the Gene Profiling Shared Resource for technical help and useful discussions. This work was supported by US NIH grant R00HL112962, R56HL137779, and an innovative research grant from the American Heart Association (17IRG33400218) all to S.A.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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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U2 - 10.1038/s41419-018-0690-y
DO - 10.1038/s41419-018-0690-y
M3 - Article
C2 - 29795397
AN - SCOPUS:85047653559
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 6
M1 - 632
ER -