The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress.
Nucleic Acids Res
; 51(5): 2298-2318, 2023 03 21.
Article
em En
| MEDLINE
| ID: mdl-36807739
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Diabetes Mellitus
/
Componente 2 do Complexo de Manutenção de Minicromossomo
/
Receptor para Produtos Finais de Glicação Avançada
/
Neoplasias
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Nucleic Acids Res
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Alemanha