MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling.
MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence, and angiogenic signaling.
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DOI：
10.1038/s41419-018-0690-y
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发表时间：
2018-05-24
影响因子：
9
通讯作者：
Anand S
中科院分区：
文献类型：
--
作者：
Espinosa-Diez C;Wilson R;Chatterjee N;Hudson C;Ruhl R;Hipfinger C;Helms E;Khan OF;Anderson DG;Anand S
微小RNA（miR）通过缓冲细胞过程免受外部扰动而有助于生物稳健性。在这里，我们报告了一个意外的DNA损伤反应和血管生成信号之间的联系，是由一个miR缓冲。我们证明了遗传毒性应激诱导的miR-494通过靶向MRE 11 a-RAD 50-NBN（MRN）复合物抑制DNA修复机制。功能获得和丧失实验表明，miR-494加剧了DNA损伤并驱动内皮衰老。miR-494的增加影响端粒酶活性，激活p21，减少pRb通路，并减少血管生成发芽。MRN通路的遗传和药理学破坏降低VEGF信号传导，表型模仿miR-494诱导的衰老，并破坏血管生成发芽。血管靶向递送miR-494在小鼠模型中降低生长因子诱导的血管生成和肿瘤血管生成。我们的工作确定了一个假定的miR促进机制，通过该机制，内皮细胞可以与VEGF信号传导隔离，以促进衰老的发生，并突出了靶向DNA修复破坏病理性血管生成的潜力。
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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