Age Dependent Accumulation of Spontaneous DNA Damage in Liver ofTransgenic Mice over Expressing Ribosomal Protein S3

Oxidative stress has been associated with the aging process and increased cancer incidence mainly due to accumulation of free radical dependent cellular damage. Reactive oxygen species (ROS) induced formation of 7,8-dihydro-8-oxoguanine (8-oxodG) has the potential to mispair with Adenine during DNA replication in key genes involved in the development of cancer. Human ribosomal protein S3 (RPS3) participates in a variety of reactions beyond its role in protein synthesis, such as processing of oxidative DNA damage. We have shown ex vivo that oxidative stress causes RPS3 to translocate to the nucleus, bind to sites of 8-oxodG with an extraordinarily high binding affinity and interferes with 8-oxodG repair in vitro. Furthermore, our in vivo studies using RPS3 over expressing transgenic mice showed translocation of RPS3 to the nucleus in mouse embryonic fibroblasts (MEFs) and co-localization to 8-oxodG foci with an increase in DNA damage. In this study, we show age dependent accumulation of DNA damage (double strand breaks [DSBs] and fragmented DNA) in aging (15-month old) transgenic mice over expressing RPS3. We also observed increase in DNA damage particularly 8-oxodG, in the liver of older transgenic mice which showed a pre-neoplastic pathology and presence of hepatic tumors. The older transgenic livers had significantly higher p53 expression compared to age matched wild-type mice. These results provide evidence for role of RPS3 over expression interfering with DNA repair and predisposing animals to carcinogenesis but also underscore the role of RPS3 expression plays in the DNA damage signaling pathway and in maintenance of genome integrity by channeling cells either towards cell survival (DNA repair) or cell death (apoptosis).