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

Zhe Han1, Martin Andrš2,3, Bindhu K Madhavan1

  • 1Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany.

Nucleic Acids Research
|February 22, 2023
PubMed

Insights

Receptor for Advanced Glycated Endproducts (RAGE) stabilizes DNA replication forks under metabolic stress. RAGE deficiency impairs DNA replication, leading to organ damage in diseases like diabetes and cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA replication defects are linked to diabetes and cancer.
  • The role of nuclear perturbations in organ complications is not well understood.

Purpose of the Study:

  • To investigate the role of Receptor for Advanced Glycated Endproducts (RAGE) in DNA replication under metabolic stress.
  • To explore the link between RAGE, DNA replication, and organ complications in disease.

Main Methods:

  • Investigated RAGE localization and interaction with the minichromosome-maintenance (Mcm2-7) complex upon metabolic stress.
  • Assessed the impact of RAGE deficiency on DNA replication fork progression, viability, and organ integrity.
  • Examined the RAGE-Mcm2 axis in human biopsies and mouse models of diabetic nephropathy and cancer.

Main Results:

  • RAGE localizes to damaged replication forks and stabilizes the Mcm2-7 complex under metabolic stress.
  • RAGE deficiency results in slowed fork progression, fork collapse, hypersensitivity to replication stress, and reduced viability.
  • RAGE deficiency leads to markers of organ damage, including micronuclei, loss of ciliated zones, tubular-karyomegaly, and interstitial fibrosis.
  • The RAGE-Mcm2/7 axis is compromised in micronucleated cells in diabetic nephropathy and cancer models.

Conclusions:

  • The RAGE-Mcm2/7 axis is crucial for managing replication stress in vitro.
  • This axis plays a critical role in preventing organ damage associated with diseases like diabetes and cancer.

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