Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair
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)-rep...
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| Hauptverfasser: | , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
09 August 2017
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| In: |
Nucleic acids research
Year: 2017, Jahrgang: 45, Heft: 18, Pages: 10595-10613 |
| ISSN: | 1362-4962 |
| DOI: | 10.1093/nar/gkx705 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1093/nar/gkx705 Verlag, kostenfrei, Volltext: https://academic.oup.com/nar/article/45/18/10595/4079821 
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| Verfasserangaben: | Varun Kumar, Thomas Fleming, Stefan Terjung, Christian Gorzelanny, Christoffer Gebhardt, Raman Agrawal, Marcus A. Mall, Julia Ranzinger, Martin Zeier, Thati Madhusudhan, Satish Ranjan, Berend Isermann, Arthur Liesz, Divija Deshpande, Hans-Ulrich Häring, Subrata K. Biswas, Paul R. Reynolds, Hans-Peter Hammes, Rainer Peperkok, Peter Angel, Stephan Herzig, Peter P. Nawroth |
| Zusammenfassung: | 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 Serine376 and Serine389 by the ATM kinase and is recruited to the site of DNA-DSBs via an early DNA damage response. nRAGE preferentially co-localized with the MRE11 nuclease subunit of the MRN complex and orchestrates its nucleolytic activity to the ATR kinase signaling. This promotes efficient RPA2S4-S8 and CHK1S345 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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| Beschreibung: | Gesehen am 22.11.2017 |
| Beschreibung: | Online Resource |
| ISSN: | 1362-4962 |
| DOI: | 10.1093/nar/gkx705 |