Tumorigenic p53S Balances Aging and Tumorigenesis via Regulating DREAM/MMB and its Downstream Telomere DNA Replication Pathways

The Werner Syndrome (WS) is characterized with both premature aging and tumorigenic phenotypes. We introduced a tumorigenic mutation p53S found in immortalized WS mouse embryo fibroblasts (MEFs) back into WS mice to investigate the impact of p53S in telomere dysfunction induced aging process. We found that the introduction of p53S rescued the aging phenotypes of Werner syndrome, showing as the extension of life span, and the delay of organ degeneration. Further studies revealed that the introduction of p53S transcriptionally upregulated DREAM/MMB pathway and its downstream DNA helicase and telomere maintenance proteins, and facilitated the recruitment of these proteins to G4 DNA structures and DNA replication forks, which compensated the loss of Wrn and telomerase function and solved the DNA replication, telomere lengthening, and cell proliferation problems via unwinding G4 structures, which ultimately, rescue the aging phenotypes of WS. Together, our data reveal that certain features of tumorigenesis can be applied to balance with premature aging, rescue aging phenotype without tumor risk. This study suggests a new mechanism and potential tumor-free longevity strategy in aging regulation.