DNA复制缺陷的高频率与糖尿病和癌症有关。然而，将这些核扰动与器官并发症的发病或进展联系起来的数据仍未经过探索。在这里，我们报告了先前认为是细胞外受体的AGE (高级糖基化终产物受体)，在代谢应激时定位到损伤的叉中。在那里，它与稳定微染色体维护(Mcm2-7)复合物相互作用。因此，RAGE缺陷会导致减缓叉前进，过早的叉坍塌，对复制压力剂的过敏性和细胞存活能力的降低，而这些可以通过重构RAGE来逆转。这可以通过53BP1/OPT结构域的表达和微核的存在、纤毛区过早丢失的增加、管型巨核增生的发生率增加，最后是间质纤维化的表现。更重要的是，RAGE-Mcm2轴在人类活检和糖尿病性肾病和癌症的小鼠模型中表达微核的细胞中被选择性地破坏。因此，在体外和人类疾病中，功能性的RAGE-Mcm2/7轴对于处理复制压力至关重要。©作者2023年。由牛津大学出版社代表核酸研究出版。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.