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

0570756 - ÚMG 2024 RIV GB eng J - Journal Article
Han, Z. - Andrš, Martin - Madhavan, B. K. - Kaymak, S. - Sulaj, A. - Kender, Z. - Kopf, S. - Kihm, L. - Pepperkok, R. - Janščák, Pavel - Nawroth, P. - Kumar, V.
The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress.
Nucleic Acids Research. Roč. 51, č. 5 (2023), s. 2298-2318. ISSN 0305-1048. E-ISSN 1362-4962
R&D Projects: GA ČR GA22-08294S
Institutional support: RVO:68378050
Keywords : GLYCATION END-PRODUCTS * DNA-DAMAGE * GENE ATR * RECEPTOR * RAGE * COLOCALIZATION * CELLS * MUS81 * MECHANISMS * PROTEINS
OECD category: Biochemistry and molecular biology
Impact factor: 14.9, year: 2022
Method of publishing: Open access
https://academic.oup.com/nar/article/51/5/2298/7049327?login=true

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.
Permanent Link: https://hdl.handle.net/11104/0342098