2008 AFAR Research Grant: Human Ribosomal Protein S3 (hS3): Roles in Accelerated Aging and Tumorigenesis by Blocking DNA Repair in vivo

Please give a brief summary of your AFAR research project.
A common genetic lesion likely to be involved in the onset of many cancers and age related disorders is formed by oxidative stress due to biological, chemical and environmental factors. In humans, the removal of this lesion is not as efficient as seen in other organisms, especially in certain tissues such as the lung. We have found that the human ribosomal protein S3 binds tightly to this genetic lesion and, in fact interferes with its repair. We have also shown that S3 can positively influence some of the important genes involved in the repair of this lesion. In the proposed research project we will be conducting studies on genetically engineered mice that were created to produce increased levels of S3, which would help us in understanding the role of this protein in the process of aging and cancer development in animals.

What problems are you addressing and what specific questions will your research seek to answer?
The proposed research project seeks to, 1) Determine whether S3 affects repair of a common genetic lesion and aberrant cell survival and tumor development in vivo and 2) Identify the cellular processes involved in the inhibition of DNA repair by S3 in response to oxidative stress.

We believe in situations of overwhelming DNA damage to cells S3 might be functioning as a sentinel to prevent promiscuous DNA repair which would cause wide spread DNA breaks as an intermediate of the DNA repair process. By blocking DNA repair S3 is allowing the cell to activate cell cycle checkpoints to slow down the cell cycle and cell growth in order to repair the mutant bases or channel the cell towards programmed cell death thereby maintaining the integrity of the genome.

What aspects of your project are most interesting from a scientific point of view?
Since the biochemical, molecular and cellular studies thus far were performed in vitro, characterizing the role of ribosomal protein S3 in DNA repair and aging beyond its participation in protein synthesis in the whole animal is most interesting. Identification of its interactions with other proteins, the role of its involvement with repair proteins and other signal transduction networks that hS3 plays a role in are especially important.

What are the implications of your research for age-related diseases and disorders?
Our in vitro observations with RNA interference having a positive effect on survival might be important in aging as in a recent study 2700 essential genes in Caenorhabditis elegans were screened for increased adult lifespan by initiating the gene knockdown once the animal had reached adulthood. 64 genes were identified that can extend lifespan when inactivated and genes involved in protein synthesis caused the most potent lifespan change. Interestingly this study found that rps3 (hS3) was one of the three clones that target components of the 40S subunit of the ribosome and increased mean lifespan.

The in situ examination of S3 in tissues and in vivo in animals will help our understanding of how this ribosomal protein might be involved or influences the aging process.

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