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Kumar, Varun [VerfasserIn]; Fleming, Thomas [VerfasserIn]; Gorzelanny, Christian [VerfasserIn]; Agrawal, Raman [VerfasserIn]; Mall, Marcus A. [VerfasserIn]; Ranzinger, Julia [VerfasserIn]; Zeier, Martin [VerfasserIn]; Deshpande, Divija [VerfasserIn]; Hammes, Hans-Peter [VerfasserIn]; Herzig, Stephan [VerfasserIn]; Nawroth, Peter Paul [VerfasserIn]

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

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  • Medientyp: E-Artikel
  • Titel: Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair
  • Beteiligte: Kumar, Varun [VerfasserIn]; Fleming, Thomas [VerfasserIn]; Gorzelanny, Christian [VerfasserIn]; Agrawal, Raman [VerfasserIn]; Mall, Marcus A. [VerfasserIn]; Ranzinger, Julia [VerfasserIn]; Zeier, Martin [VerfasserIn]; Deshpande, Divija [VerfasserIn]; Hammes, Hans-Peter [VerfasserIn]; Herzig, Stephan [VerfasserIn]; Nawroth, Peter Paul [VerfasserIn]
  • Erschienen: 09 August 2017
  • Erschienen in: Nucleic acids research ; 45(2017), 18, Seite 10595-10613
  • Sprache: Englisch
  • DOI: 10.1093/nar/gkx705
  • ISSN: 1362-4962
  • Identifikator:
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: 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.
  • Zugangsstatus: Freier Zugang