Scientists from seven research institutes, including the University of Oxford and the University of Edinburgh, have used pioneering bioinformatics modeling to study the molecular interactions of the p53 protein known to offer protection against cancers.
The research, published in Molecular biology and evolutionprovides new insights into molecular interactions that could help people become less prone to cancer.
Cells are regularly replicated, new cells replacing old ones, and each new cell contains new copies of DNA. These new cells should be exact copies of older cells, but mutations occur if proteins replicate and transcribe DNA by mistake. Most errors are immediately repaired by the cell, although the number of mutations and the quality of repairs are affected by both genetic and external/living circumstances. Toxic compounds, stress, poor living conditions, and aging can all increase the rate of mutation.
Tumors resulting from the accumulation of such genetic mutations increase the risk with age – but unlike humans, elephants seem to reverse this trend. Despite their large body size and life expectancy comparable to humans, cancer mortality in elephants is estimated to be less than 5% (rather than up to 25% in humans). Scientists link elephants’ high resistance to cancer to their 20 copies of the p53 gene – the “keeper of the genome” – compared to the single p53 gene found in other mammals.
Co-author Professor Fritz Vollrath, Biology department, Oxford University and administrator of Save the Elephants said: “This complex and intriguing study shows how elephants are so much more than impressive size and how important it is not only to conserve but also to study these iconic animals in great detail. After all, their genetics and physiology are all influenced by evolutionary history as well as today’s ecology, diet and behavior.
P53 plays a key role in regulating DNA repair mechanisms and suppresses uncontrolled cell growth. The protein activates when DNA is damaged and helps orchestrate a response that interrupts DNA replication and repairs all uncorrected copies of the cell. In cells replicated with undamaged DNA, p53 repair activity is not required and is inactivated by another protein, the oncogene MDM2 E3 ubiquitin ligase.
The regulated interaction, or handshake, between p53 – MDM2 is essential for the division and replication of healthy cells, the repair of damaged cells, and the destruction of cells whose repairs have failed or which have undergone damage. significant damage.
The elephant may seem genetically over-endowed with 40 alleles, or versions, of its twenty p53 genes, but each is structurally slightly different, giving an elephant a much wider range of molecular cancer-fighting interactions than a human with just two. alleles of a single gene.
Using biochemical analyzes and computer simulations, the researchers found key differences in the handshake interaction between the different elephant p53 isoforms and MDM2.
Minor variations in molecular sequence result in a different molecular structure for each of the p53 molecules. The small structural differences alter the three-dimensional shape of the isoform and significantly alter the handshake function between p53 and MDM2.
The research team found that due to changes in coding sequences and molecular structure, a number of p53s escaped the interaction with MDM2 that would normally lead to their inactivation. The results are the first to show that the different p53 isoforms found in elephants are not degraded or inactivated by MDM2 – unlike humans.
Co-author Professor Robin Fåhraeus, INSERM, Paris, said: “This is an exciting development for our understanding of how p53 helps prevent cancer development. In humans, the same p53 protein is responsible for deciding whether cells should stop proliferating or enter apoptosis, but how p53 makes this decision has been difficult to elucidate. The existence of multiple p53 isoforms in elephants with different abilities to interact with MDM2 offers an exciting new approach to shed new light on the tumor suppressor activity of p53.
Understanding more about how p53 molecules are activated and when this can lead to increased sensitivity and response against carcinogenic conditions is an exciting prospect for further research into p53 activation and targeted drug therapies in humans.
Corresponding author, Dr Konstantinos Karakostis, from the Autonomous University of Barcelona, noted: “Conceptually, the accumulation of structurally modified pools of p53, collectively or synergistically co-regulating responses to various stresses in the cell, establishes an alternative mechanistic model of cellular regulation with high potential importance for biomedical applications.
Reference: Padariya M, Jooste ML, Hupp T, et al. The elephant has evolved p53 isoforms that escape MDM2-mediated repression and cancer. Mol Bio and Evo. 2022;39(7):msac149. do I: 10.1093/molbev/msac149.
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