This month in DNA repair: the elephant and the prize
Evolution’s War on Cancer
In 1977, Oxford professor of medical statistics and epidemiology Richard Peto described a paradox – Peto’s Paradox – in which humans and mice have the same overall risk of cancer despite their enormous disparity in lifetime cell divisions. Increases in body size and lifespan should theoretically make an animal more prone to DNA replication errors that can produce cancer-causing mutations. African elephants, weighing up to 12,000 pounds and living up to 70 years, should be riddled with tumors, yet somehow they live long, cancer-free lives.
Dr. Joshua Schiffman’s group at the Huntsman Cancer Institute in Salt Lake City, Utah, has just published an intriguing study of elephant genetics and cell biology in the Journal of the American Medical Association (JAMA) this month. First, using many years of data from the San Diego Zoo, these scientists found absolutely no correlation between lifespan and the percent of death attributed to cancer across 36 species of various captive mammals. In fact, most mammals had a 5-8% of cancer-related death, from the tree shrew to koala to lion to elephant.
Performing a genome-wide analysis revealed that elephants carried not two copies of the tumor-suppressor gene p53, as humans do, but a whopping twenty copies (ten on each chromosome)! One of these copies was homologous to ours, while the other 19 were retrogene copies, or genes that were copied from RNA back to DNA by reverse transcription and re-inserted into the genome. The authors of this study then collected peripheral blood cells from elephants and humans, and subjected them to DNA-damaging agents including the drug doxorubicin and ionizing irradiation, and quantified the efficiency of DNA damage repair by looking at markers of DNA damage, cell cycle arrest and cell death. While elephant and human cells both underwent DNA damage, and both induced p53 protein expression in response to that damage (to turn on cell cycle arrest and DNA repair mechanisms), elephant cells were much more prone to apoptosis, or cellular death.
Apoptosis is a pretty thorough way of wiping out potentially dangerous mutations, and these authors proposed that apoptosis is especially important in such rapidly-growing animals as baby elephants, who gain more than a kilogram of weight per day. While it’s clear from this study that evolutionary genetics has bestowed elephants with a powerful anti-cancer mechanism, the authors do note that environmental factors will ultimately affect elephants just as they do humans, stating that “it is unclear how captivity influences cancer rates through diet, stress, physical activity, and reproduction.” They will also need to look into whether the extra 19 p53 retrogenes actually produce functional proteins, and do quite a bit more work on elephant cell biology, before they figure out the full mechanism of their intriguing observations.
Sources: JAMA, New York Times
Nobel Prize in Chemistry
The 2015 prize in chemistry was awarded earlier this month jointly to Tomas Lindahl (Francis Crick Institute), Paul Modrich (Duke and HHMI) and Aziz Sancar (UNC Chapel Hill) for “[mapping], at a molecular level, how cells repair damaged DNA and safeguard the genetic information.” The DNA damage response (DDR) program protects our cells from the damage caused by various environmental factors including mutagenic chemicals, radiation and free radicals (reactive uncharged molecules). It also catches and fixes the random mistakes that occur stochastically throughout a lifetime of DNA replication for cell division. These three award winners discovered and described the processes of excision and mismatch repair that hold our DNA to a high proofreading standard.
Although the DDR program was first discovered decades ago, research groups are still characterizing the intricacies of this enormous cellular program. A recent publication in Molecular Cell from Dr. Stephen Elledge’s group at Harvard Medical School used a proteomic approach to analyze protein modifications (phosphorylation, ubiquitination and acetylation) that occur in a cell in response to ultraviolet and ionizing radiation. Among the large data set produced by this study was the finding that the DDR regulates the mitotic spindle and by extension cell division through ubiquitination events (the addition of ubiquitin groups to proteins). The authors also found differences in ubiquitination events that depended on the type of radiation that had caused the DDR in the first place, suggesting a whole new level of complexity to this Nobel-recognized process.
Sources: Nobel Prize, Molecular Cell
Hanna Starobinets is a 5th year Biomedical Sciences PhD Student.
