The importance of nuclear RAGE-Mcm2 axis in diabetes or cancer-associated replication stress.
Zhe HanMartin AndršBindhu K MadhavanSerap KaymakAlba SulajZoltan KenderStefan KopfLars KihmRainer PepperkokPavel JanscakPeter NawrothVarun KumarPublished in: Nucleic acids research (2023)
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.
Keyphrases
- endothelial cells
- diabetic nephropathy
- type diabetes
- papillary thyroid
- cardiovascular disease
- stress induced
- binding protein
- mouse model
- induced apoptosis
- glycemic control
- poor prognosis
- squamous cell
- induced pluripotent stem cells
- electronic health record
- machine learning
- metabolic syndrome
- big data
- cell proliferation
- cell cycle arrest
- oxidative stress
- artificial intelligence
- cell death
- lymph node metastasis
- pi k akt