PT  - JOURNAL ARTICLE
AU  - Cristina Espinosa-Diez
AU  - RaeAnna Wilson
AU  - Namita Chatterjee
AU  - Clayton Hudson
AU  - Rebecca Ruhl
AU  - Christina Hipfinger
AU  - Erin Helms
AU  - Omar F. Khan
AU  - Daniel G. Anderson
AU  - Sudarshan Anand
TI  - MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling
AID  - 10.1101/132258
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 132258
4099  - http://biorxiv.org/content/early/2018/01/18/132258.short
4100  - http://biorxiv.org/content/early/2018/01/18/132258.full
AB  - MicroRNAs 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 two distinct microRNAs. We demonstrate that genotoxic stress-induced miR-494 and miR-99b inhibit the DNA repair machinery by targeting the MRE11a-RAD50-NBN (MRN) complex. Functionally, gain and loss of function experiments show that miR-494 and miR-99b affect telomerase activity, activate p21 and Rb pathways and diminish angiogenic sprouting in vitro and in vivo. Genetic and pharmacological disruption of VEGFR-2 signaling and the MRN complex reveal a surprising co-dependency of these pathways in regulating endothelial senescence and proliferation. Vascular-targeted delivery of miR-494 decreases both growth factor-induced and tumor angiogenesis in mouse models. Mechanistically, disruption of the MRN complex induced CD44, a known driver of senescence and regulator of VEGF signaling in addition to suppressing IL-13 a stimulator of VEGF signaling. 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.