Evolution of human genome's 'guardian' gives people unique protections from DNA damage

Human evolution has created enhancements in key genes connected to the p53 regulatory network - the so-called guardian of the genome - by creating additional safeguards in human genes to boost the network's ability to guard against DNA damage that could cause cancer or a variety of genetic diseases, an international team of scientists led by Cincinnati Children's Hospital Medical Center writes in the Jan. 22 Proceedings of the National Academy of Sciences. Because genetically engineered mouse models are increasingly powerful tools in understanding the risks and mechanisms of human diseases - and rodents do not have the same evolution-based safeguards in p53 function as humans - the study also underscores the need for additional considerations in the interpretation of research using rodent models.

"Our findings are especially important because rodents are often used as model organisms to investigate the genetic origins of diseases that affect humans, such as cancer investigators evaluating the impact of DNA-damaging agents," said Anil Jegga, DVM, a researcher in the Division of Biomedical Informatics at Cincinnati Children's. "Rodent models remain important to our understanding of disease processes, although our study suggests the need to address experimentally the differences in p53 regulatory pathways between humans and rodent models."

In the study, Jegga and his colleagues used comparative functional genomics to look systematically at small DNA sequences associated with the promoters, or enhancers, of specific genes that carry out orders from p53. These promoter elements act like antennae - responding to activated p53 by boosting target gene expression and function inside a cell's nucleus. By comparing these response elements across nearly 50 different binding sites of genes in the p53 network, and looking specifically at genes that repair DNA damage in 14 species (from zebra fish to humans), researchers were able to reveal critical evolutionary changes in their function. The 14 species represented an estimated 500 million years of evolutionary separation, helping investigators determine how the function of p53 response elements was conserved or changed as different species developed. Dr. Jegga said researchers were surprised to find the acquisition of functional response for certain genes involved in DNA metabolism or repair to be mostly unique in humans. While the functional ability of some genes is shared with chimpanzees and rhesus monkeys, researchers said DNA metabolism and repair function it is not shared at all with rodents.

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