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

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Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. / Kumar, Varun; Fleming, Thomas; Terjung, Stefan; Gorzelanny, Christian; Gebhardt, Christoffer; Agrawal, Raman; Mall, Marcus A; Ranzinger, Julia; Zeier, Martin; Madhusudhan, Thati; Ranjan, Satish; Isermann, Berend; Liesz, Arthur; Deshpande, Divija; Häring, Hans-Ulrich; Biswas, Subrata K; Reynolds, Paul R; Hammes, Hans-Peter; Peperkok, Rainer; Angel, Peter; Herzig, Stephan; Nawroth, Peter P.

in: NUCLEIC ACIDS RES, Jahrgang 45, Nr. 18, 13.10.2017, S. 10595-10613.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Kumar, V, Fleming, T, Terjung, S, Gorzelanny, C, Gebhardt, C, Agrawal, R, Mall, MA, Ranzinger, J, Zeier, M, Madhusudhan, T, Ranjan, S, Isermann, B, Liesz, A, Deshpande, D, Häring, H-U, Biswas, SK, Reynolds, PR, Hammes, H-P, Peperkok, R, Angel, P, Herzig, S & Nawroth, PP 2017, 'Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair', NUCLEIC ACIDS RES, Jg. 45, Nr. 18, S. 10595-10613. https://doi.org/10.1093/nar/gkx705

APA

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., ... Nawroth, P. P. (2017). Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. NUCLEIC ACIDS RES, 45(18), 10595-10613. https://doi.org/10.1093/nar/gkx705

Vancouver

Kumar V, Fleming T, Terjung S, Gorzelanny C, Gebhardt C, Agrawal R et al. Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. NUCLEIC ACIDS RES. 2017 Okt 13;45(18):10595-10613. https://doi.org/10.1093/nar/gkx705

Bibtex

@article{97f0d6215bb543a29fc4f2637dc55db8,
title = "Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair",
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.",
keywords = "Animals, Ataxia Telangiectasia Mutated Proteins, Cell Nucleus, Cellular Senescence, DNA, DNA Breaks, Double-Stranded, DNA Repair, DNA Repair Enzymes, DNA-Binding Proteins, Homeostasis, Lung, MRE11 Homologue Protein, Mice, Inbred C57BL, Mice, Knockout, Pulmonary Fibrosis, Receptor for Advanced Glycation End Products, Reperfusion Injury, Signal Transduction, Journal Article",
author = "Varun Kumar and Thomas Fleming and Stefan Terjung and Christian Gorzelanny and Christoffer Gebhardt and Raman Agrawal and Mall, {Marcus A} and Julia Ranzinger and Martin Zeier and Thati Madhusudhan and Satish Ranjan and Berend Isermann and Arthur Liesz and Divija Deshpande and Hans-Ulrich H{\"a}ring and Biswas, {Subrata K} and Reynolds, {Paul R} and Hans-Peter Hammes and Rainer Peperkok and Peter Angel and Stephan Herzig and Nawroth, {Peter P}",
note = "{\textcopyright} The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.",
year = "2017",
month = oct,
day = "13",
doi = "10.1093/nar/gkx705",
language = "English",
volume = "45",
pages = "10595--10613",
journal = "NUCLEIC ACIDS RES",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "18",

}

RIS

TY - JOUR

T1 - Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair

AU - Kumar, Varun

AU - Fleming, Thomas

AU - Terjung, Stefan

AU - Gorzelanny, Christian

AU - Gebhardt, Christoffer

AU - Agrawal, Raman

AU - Mall, Marcus A

AU - Ranzinger, Julia

AU - Zeier, Martin

AU - Madhusudhan, Thati

AU - Ranjan, Satish

AU - Isermann, Berend

AU - Liesz, Arthur

AU - Deshpande, Divija

AU - Häring, Hans-Ulrich

AU - Biswas, Subrata K

AU - Reynolds, Paul R

AU - Hammes, Hans-Peter

AU - Peperkok, Rainer

AU - Angel, Peter

AU - Herzig, Stephan

AU - Nawroth, Peter P

N1 - © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2017/10/13

Y1 - 2017/10/13

N2 - 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.

AB - 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.

KW - Animals

KW - Ataxia Telangiectasia Mutated Proteins

KW - Cell Nucleus

KW - Cellular Senescence

KW - DNA

KW - DNA Breaks, Double-Stranded

KW - DNA Repair

KW - DNA Repair Enzymes

KW - DNA-Binding Proteins

KW - Homeostasis

KW - Lung

KW - MRE11 Homologue Protein

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Pulmonary Fibrosis

KW - Receptor for Advanced Glycation End Products

KW - Reperfusion Injury

KW - Signal Transduction

KW - Journal Article

U2 - 10.1093/nar/gkx705

DO - 10.1093/nar/gkx705

M3 - SCORING: Journal article

C2 - 28977635

VL - 45

SP - 10595

EP - 10613

JO - NUCLEIC ACIDS RES

JF - NUCLEIC ACIDS RES

SN - 0305-1048

IS - 18

ER -