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
Abstract 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.
Espinosa-Diez Cristina、Anderson Daniel G.、Helms Erin、Hipfinger Christina、Wilson RaeAnna、Ruhl Rebecca、Chatterjee Namita、Hudson Clayton、Anand Sudarshan、Khan Omar F.
Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Chemical Engineering, Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyDepartment of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Cell, Developmental and Cancer Biology, Department of Radiation Medicine, Oregon Health and Sciences University (OHSU)Department of Chemical Engineering, Institute for Medical Engineering and Science, David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
基础医学分子生物学生物化学
microRNAsenescenceDNA repairMRN complexangiogenesis
Espinosa-Diez Cristina,Anderson Daniel G.,Helms Erin,Hipfinger Christina,Wilson RaeAnna,Ruhl Rebecca,Chatterjee Namita,Hudson Clayton,Anand Sudarshan,Khan Omar F..MicroRNA regulation of the MRN complex impacts DNA damage, cellular senescence and angiogenic signaling[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/132258.点此复制
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