CompromisedDNArepair is responsible for diabetes‐associated fibrosis
Open Access
- 27 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 39 (11), e103477
- https://doi.org/10.15252/embj.2019103477
Abstract
Diabetes‐associated organ fibrosis, marked by elevated cellular senescence, is a growing health concern. Intriguingly, the mechanism underlying this association remained unknown. Moreover, insulin alone can neither reverse organ fibrosis nor the associated secretory phenotype, favoring the exciting notion that thus far unknown mechanisms must be operative. Here, we show that experimental type 1 and type 2 diabetes impairs DNA repair, leading to senescence, inflammatory phenotypes, and ultimately fibrosis. Carbohydrates were found to trigger this cascade by decreasing the NAD+/NADH ratio and NHEJ‐repair in vitro and in diabetes mouse models. Restoring DNA repair by nuclear over‐expression of phosphomimetic RAGE reduces DNA damage, inflammation, and fibrosis, thereby restoring organ function. Our study provides a novel conceptual framework for understanding diabetic fibrosis on the basis of persistent DNA damage signaling and points to unprecedented approaches to restore DNA repair capacity for resolution of fibrosis in patients with diabetes.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (SFB1118, GRK 1874‐DIAMICOM)
This publication has 122 references indexed in Scilit:
- Association between DNA strand breakage and oxidative, inflammatory and endothelial biomarkers in type 2 diabetesMutation research. Reviews in mutation research, 2012
- Linking mitochondrial bioenergetics to insulin resistance via redox biologyTrends in Endocrinology & Metabolism, 2012
- Regulation of DNA-End Resection by hnRNPU-like Proteins Promotes DNA Double-Strand Break Signaling and RepairMolecular Cell, 2012
- Redox-optimized ROS balance: A unifying hypothesisBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2010
- Inflammatory networks during cellular senescence: causes and consequencesTrends in Molecular Medicine, 2010
- Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretionNature, 2009
- Single-Stranded DNA Orchestrates an ATM-to-ATR Switch at DNA BreaksMolecular Cell, 2009
- Comparison of nonhomologous end joining and homologous recombination in human cellsDNA Repair, 2008
- ATR: an essential regulator of genome integrityNature Reviews Molecular Cell Biology, 2008
- Human CtIP promotes DNA end resectionNature, 2007