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.

The circadian clock protects against ionizing radiation‐induced cardiotoxicity

“…These can also be linked to DNA repair mechanisms as a recent study showed that the Atm kinase-dependent function of the nuclear isoform of the Receptor for Advanced Glycation End-products (nRAGE) plays a critical role in DSB repair to prevent pulmonary fibrosis. 60 Our clock-disrupted models were more sensitive to IR-induced loss of cardiac function possibly through p53-and Atm-mediated DDR mechanisms. To confirm this mechanism, our experimental ChIP assay and ChIP-Seq results showed Bmal1, the positive regulator of Per1/2, transcriptionally binds to the promoters of Atm, as well as Brca1 and Brca2 genes, and Bmal1 protein levels were significantly reduced in heart samples of clock-disrupted mice (Figures 2A,B, 3 and Table 3).…”

“…Similarly, we observed the effects of IR exposure in the heart through DNA damage marker, pH2a.x, and fibrosis, which ultimately affects heart function significantly in our genetically (Per1/2 –/– ) as well as environmentally (Rotating Shift) clock‐disrupted models (Figure ). These can also be linked to DNA repair mechanisms as a recent study showed that the Atm kinase‐dependent function of the nuclear isoform of the Receptor for Advanced Glycation End‐products (nRAGE) plays a critical role in DSB repair to prevent pulmonary fibrosis . Our clock‐disrupted models were more sensitive to IR‐induced loss of cardiac function possibly through p53‐ and Atm‐mediated DDR mechanisms.…”

Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes

“…It remains to be determined whether this is related to a systemic effect on fibrosis formation in patients with diabetes. Pulmonary fibrosis has also been observed in experimental diabetes models [36-38]. Thus, diabetes itself may be associated with a generalized increased risk of fibrosis in several organs.…”

Bacteria in the ageing gut: did the taming of fire promote a long human lifespan?

“…AGE‐RAGE stress is generally perceived as negative because it involves a number of cell processes such as neuroinflammation [it is possibly a cause of Parkinson's disease (Jiang et al ., )], apoptosis and proliferation. However, it is also involved in autophagy and its nuclear form protects against DNA double strand breaks (Kumar et al ., ). In animals, defence mechanisms counteract the adverse effects of AGE‐RAGE via enzymatic degradation of AGE metabolites as well as RAGE degradation (Prasad and Mishra, ), and enhancement of the level of soluble receptor of AGE (sRAGE), which counteracts the negative impact of AGE products (Simm et al ., ).…”