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.
Highlights
Introduction Accumulation ofDNA damage can overwhelm the repair machinery and lead to senescence[1]
We found that miR-494 and miR-99b are both transcribed rapidly in human umbilical vein endothelial cells (ECs) (HUVECs) in response to γ-radiation with maximal induction occurring at 2 Gy (Fig. 1a, b)
Based on a surprising observation that miR-processing enzyme Dicer impacts EC DNA repair, we set up a screen and identified a group of seven miRs that are induced by DNA damage
Summary
DNA damage can overwhelm the repair machinery and lead to senescence[1]. Two major pathways of senescence in endothelial cells (ECs) are replicative senescence and stress-induced premature senescence (SIPS). ATM can function as a redox sensor independent of its DNA damage repair (DDR) function and regulate oxidative stress responses[5] and was recently implicated as a driver of cellular senescence[6]. Global or EC-specific deletion of the histone H2AX in mice results in a substantial decrease of pathological angiogenesis in proliferative retinopathy, hindlimb ischemia, and tumor angiogenesis. These findings suggest that key regulators of DDR modulate pathological angiogenesis
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