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Kumar, V.* ; Fleming, T.* ; Terjung, S.* ; Gorzelanny, C.* ; Gebhardt, C.* ; Agrawal, R.* ; Mall, M.A.* ; Ranzinger, J.* ; Zeier, M.* ; Madhusudhan, T.* ; Ranjan, S.* ; Isermann, B.* ; Liesz, A.* ; Deshpande, D.* ; Häring, H.-U. ; Biswas, S.K.* ; Reynolds, P.R.* ; Hammes, H.P.* ; Peperkok, R.* ; Angel, P.* ; Herzig, S. ; Nawroth, P.P.

Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair.

Nucleic Acids Res. 45, 10595-10613 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The integrity of genome is a prerequisite for healthy life. Indeed, defects in DNA repair have been associated with several human diseases, including tissue-fibrosis, neurodegeneration and cancer. Despite decades of extensive research, the spatio-mechanical processes of double-strand break (DSB)repair, especially the auxiliary factor(s) that can stimulate accurate and timely repair, have remained elusive. Here, we report an ATM-kinase dependent, unforeseen function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) in DSB-repair. RAGE is phosphorylated at Serine(376) and Serine(389) by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially colocalized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2(S4-S8) and CHK1(S345) phosphorylation and thereby prevents cellular senescence, IPF and carcinoma formation. Accordingly, loss of RAGE causatively linked to perpetual DSBs signaling, cellular senescence and fibrosis. Importantly, in a mouse model of idiopathic pulmonary fibrosis (RAGE(-/-)), reconstitution of RAGE efficiently restored DSB-repair and reversed pathological anomalies. Collectively, this study identifies nRAGE as a master regulator of DSB-repair, the absence of which orchestrates persistent DSB signaling to senescence, tissue-fibrosis and oncogenesis.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Glycation End-products; Idiopathic Pulmonary-fibrosis; Strand Break Repair; Damage-response; Ataxia-telangiectasia; Endonuclease Activity; Cellular Senescence; Cerebral-ischemia; Tumor-suppressor; Epithelial-cells
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Journal Nucleic Acids Research
Quellenangaben Volume: 45, Issue: 18, Pages: 10595-10613 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Diabetes Research and Metabolic Diseases (IDM)