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

• Verfasst von: Kumar, Varun [VerfasserIn]
• Verfasst von: Fleming, Thomas [VerfasserIn]
• Verfasst von: Gorzelanny, Christian [VerfasserIn]
• Verfasst von: Agrawal, Raman [VerfasserIn]
• Verfasst von: Mall, Marcus A. [VerfasserIn]
• Verfasst von: Ranzinger, Julia [VerfasserIn]
• Verfasst von: Zeier, Martin [VerfasserIn]
• Verfasst von: Deshpande, Divija [VerfasserIn]
• Verfasst von: Hammes, Hans-Peter [VerfasserIn]
• Verfasst von: Herzig, Stephan [VerfasserIn]
• Verfasst von: Nawroth, Peter Paul [VerfasserIn]
• Titel: Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair
• Verf.angabe: 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
• E-Jahr: 2017
• Jahr: 09 August 2017
• Umfang: 19 S.
• Fussnoten: Gesehen am 22.11.2017
• Titel Quelle: Enthalten in: Nucleic acids research
• Ort Quelle: Oxford : Oxford Univ. Press, 1974
• Jahr Quelle: 2017
• Band/Heft Quelle: 45(2017), 18, Seite 10595-10613
• ISSN Quelle: 1362-4962
• DOI: doi:10.1093/nar/gkx705
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1565588789

Abstract

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.