Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, INF 410, Heidelberg, Germany.
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, CZ-14300 Prague, Czech Republic.
Nucleic Acids Res. 2023 Mar 21;51(5):2298-2318. doi: 10.1093/nar/gkad085.
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.
DNA 复制缺陷频率升高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生或进展联系起来的数据仍未得到探索。在这里，我们报告称，先前被认为是细胞外受体的 RAGE（晚期糖基化终产物受体）在代谢应激下定位于受损的叉头。在那里，它相互作用并稳定微染色体维持（Mcm2-7）复合物。因此，RAGE 缺乏会导致叉头推进速度减慢、叉头过早崩溃、对复制应激剂的敏感性增加以及活力降低，而 RAGE 的重建可逆转这些现象。这表现为 53BP1/OPT 结构域的表达和微核的存在、纤毛区过早丢失、管状巨细胞增多、间质纤维化的发生率增加。更重要的是，在人类活检和糖尿病肾病和癌症的小鼠模型中表达微核的细胞中，RAGE-Mcm2 轴选择性受损。因此，功能性 RAGE-Mcm2/7 轴在体外和人类疾病中处理复制应激至关重要。
