Additional TP53 Copies as the Cause of Reduced Cancer Risk in Elephants

Cancer is a numbers game: there is some risk per unit time of cells acquiring the necessary mutations, coupled to some risk of the immune system failing to destroy those cells before they get going in earnest. Cancer is predominantly an age-related condition because the number of mutations rises with age, the cellular environment becomes progressively more inflammatory and conducive to cancer growth, and the immune system declines in effectiveness. But if cancer is a numbers game by count of cells, why do mammals with a very large total number of cells, such as elephants and whales, have a low rate of cancer incidence? Obviously whales could not have evolved to in fact have hundreds of times the cancer incidence of humans to match the hundreds of times as many cells in their bodies. What are the mechanisms in these larger species that reduce the cancer risk per cell? Researchers are interested in this aspect of comparative biology from the perspective of determining a potential basis for new cancer prevention strategies. Here, the authors of this commentary review the evidence for low cancer risk per cell in elephants to result from extra copies of the TP53 gene:

Cancer is a genetic disease in which cells divide uncontrollably. Some of the mutations that cause cancer are inherited, but most are the results of mistakes made when DNA is copied during cell division. By the time a person reaches adulthood, their DNA will have been copied about 30 trillion times, and each of these events could result in a cancer-causing mutation. Since large, long-lived organisms experience more cell divisions than small, short-lived ones, they have a greater chance of accumulating cancer-causing mutations. Indeed, models suggest that if elephants and whales had the same risk of cancer per cell division as humans they could not exist. Instead, they would all die of cancer at a young age. Clearly elephants and whales do exist, and neither of them have unusually high rates of cancer. This puzzle is referred to as Peto's Paradox, and it hints that large-bodied animals must have mechanisms to compensate for experiencing so many cell divisions. Recently, two groups of researchers set out to discover how elephants evolved to prevent or suppress cancer, and both arrived at a single gene - TP53.

In humans, the TP53 gene protects against cancer, and mutations that prevent the gene from working are behind many cancers in adults. Last year, researchers reported a number of interesting results on TP53 genes in elephants. First they confirmed that an elephant's cancer risk is about 2-5 times lower than a human's; they then went on to show that elephants actually have 20 copies of TP53. They also noted that while one of the elephant's TP53 genes was comparable to those in other mammals, the other 19 were slightly different. Most genes contain a mix of protein coding sections (which are called exons) and non-coding sections (called introns). Typically, introns are removed after a gene has been transcribed into messenger RNA but before it is translated into a protein. However, all but one of the TP53 genes in elephants lacked true introns. This indicates that the 19 extra TP53 genes likely originated when an edited RNA molecule, which had had its introns removed, was converted back to DNA. Genes with this kind of history are known as "retrogenes". One way that the TP53 gene protects against cancer is by causing cells with damaged DNA (which is likely to contain cancer-causing mutations) to commit suicide, via a process known as apoptosis. The researchers exposed elephant cells to ionizing radiation (which causes DNA damage) and found that they were twice as likely to undergo apoptosis as cells from healthy humans. However, based on this pair-wise comparison, it was not clear whether the elephant cells are more prone to apoptosis, or if human cells are relatively insensitive to DNA damage.

Now another team report answers to many of the remaining open questions about TP53 in elephants. First they searched 61 genomes of animals ranging from aardvarks to whales for TP53 genes and retrogenes. Some of these animals - such as manatees and the rock hyrax - had only a few TP53 retrogenes, whereas others had multiple copies of TP53 retrogenes. By mapping the data onto a phylogenetic tree, the researchers showed that the number of TP53 genes had increased as body size increased in the lineage that led to elephants. They confirmed that some of the TP53 retrogenes are transcribed and translated in elephant tissue, and that these transcripts give rise to multiple forms of the proteins. Also, elephant cells up-regulated TP53 signaling and induced apoptosis in response to lower levels of DNA damage (from drugs and radiation) than cells from other mammals. This indicates that elephant cells are especially sensitive to DNA damage and more prone to apoptosis. Next, the researchers showed that elephant cells need the retrogenes for their enhanced apoptosis response. Finally, adding the same retrogenes to mouse cells made these cells more sensitive to DNA damage too. Cell division despite DNA damage is a hallmark of cancer, and so the researchers concluded that elephants had likely solved Peto's Paradox (at least in part) by enhancing TP53 signaling, a feat that they achieved by duplicating the TP53 gene.



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