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The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress

Z. Han, M. Andrš, BK. Madhavan, S. Kaymak, A. Sulaj, Z. Kender, S. Kopf, L. Kihm, R. Pepperkok, P. Janscak, P. Nawroth, V. Kumar

. 2023 ; 51 (5) : 2298-2318. [pub] 2023Mar21

Language English Country England, Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc23003767

An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.

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$a An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.
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$a Andrš, Martin $u Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, CZ-14300 Prague, Czech Republic $u Institute of Molecular Cancer Research, University of Zurich, 8057 Zurich, Switzerland $7 xx0315711
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$a Madhavan, Bindhu K $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany
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$a Kender, Zoltan $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany $u German Center of Diabetes Research (DZD), Neuherberg, Germany
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$a Kopf, Stefan $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany $u German Center of Diabetes Research (DZD), Neuherberg, Germany
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$a Kihm, Lars $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany
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$a Nawroth, Peter $u Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany $u Institute for Immunology, University Hospital of Heidelberg, INF 305, Heidelberg, Germany $u German Center of Diabetes Research (DZD), Neuherberg, Germany
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