Elephant genetics would explain why these animals rarely get cancer

Scientists from seven international institutions investigated the molecular interactions of p53 protein, known to protect against cancer. The work was coordinated by Konstantinos Karakostisresearcher Maria Zambrano from the Institute of Biotechnology and Biomedicine at the Universitat Autònoma de Barcelona (IBB-UAB).

When the routine replication of cells is affected by mutations, the risk of developing tumors increases, especially with age. However, unlike humans, elephants seem to resist this tendency, as it is estimated that cancer mortality in these animals is less than 5% (in humans it can reach 25%).

Scientists link the pachyderm’s resistance to its 20 copies of the p53 gene, which they call the ‘guardian of the genome’, compared to the single copy found in other mammals.

“This study shows that it is important not only to conserve these characteristic animals, but also to analyze them in detail. After all, their genetics and physiology are conditioned by evolutionary history as well as current ecology, diet and behavior.” Fritz Vollrathfrom the University of Oxford and a member of the board of directors of save the elephants.

P53, a wall against cancer

This protein is activated when DNA is damaged, directing a response that stops the replication of genetic material and repairs the cell’s corrupted copies. In replicated cells with intact DNA, p53 repair activity is unnecessary and is inactivated by another protein, ubiquitin ligase. MDM2.

The regulated interaction between both proteins is essential for healthy cells to divide and replicate, damaged cells to repair themselves, and cells with failed repairs or extensive damage to be destroyed.

The elephant may seem genetically endowed with 40 alleles, or versions, of its 20 anticancer genes, but each of these the alleles are structurally differentgiving this animal a much wider range of anticancer molecular interactions than a human with just two alleles of a single gene.

So using biochemical analyzes and computer simulationsthe researchers found important differences in the regulated interaction between the various isoforms of elephant p53 and MDM2.

The mechanism that activates the protein

Researchers have found that, as a result of changes in coding sequences and molecular structure, several p53s escape interaction with MDM2, which would normally cause it to be inactivated. The results demonstrate for the first time that the different isoforms of p53 found in the elephant are not degraded or inactivated by MDM2, unlike in humans.

“In humans, the same p53 protein is responsible for deciding whether cells should stop proliferating, but it has been difficult to figure out how it makes that decision. The existence of various isoforms of p53 in elephants, with different abilities to interact with MDM2, offers an interesting new insight into the tumor suppressor activity of p53,” he explains. Robin Fahraeusco-author of the study.

Better understand how these molecules are activated and when this can lead to increased sensitivity and response against cancerous conditions is an important prospect for research on p53 activation and targeted drug therapies in humans.

“Conceptually, the accumulation of structurally modified p53 groups, which regulate responses to various stresses in the cell, establishes an alternative model of cell regulation of great importance for potential biomedical applications”, he concludes. Karakostis, lead author of the study.