Elephants carry 20 copies of the gene nicknamed the guardian of the genome
Elephants have huge bodies and trillions of dividing cells, yet they rarely get cancer. Part of the explanation may be that they carry 20 copies of TP53, the gene for a protein called p53. Humans have one, and it is disabled in more than half of all human cancers.
p53 earned the nickname guardian of the genome by acting as a damage inspector. When DNA is harmed, p53 halts the cell cycle at the checkpoint before DNA copying begins, largely by switching on a gene for a brake protein, p21, that blocks the enzymes driving division. That pause buys time to switch on a wide range of repair machinery. If the damage is beyond fixing, p53 orders the cell to kill itself. It also drives the arrest of cells whose protective chromosome tips have worn too short, and at the tissue level it hampers tumours by suppressing the growth of new blood vessels they need.
To work, p53 must assemble into a tetramer, a pair of paired molecules. Most cancer mutations strike its DNA-binding core, disabling it, but mutations in the part that holds the tetramer together can be worse, poisoning healthy copies by locking them into useless complexes. There is a quirk in its very name: lab gels suggested a weight of 53 kilodaltons, but the real figure is 43.7, the protein's high proline content having slowed its movement through the gel. The single gene actually produces at least 12 protein variants.
Sometimes lowering p53 is useful. Human embryonic stem cells keep it low, since activating it pushes them to specialise. Cells with reduced p53 can be reprogrammed into stem cells far more efficiently, and dropping p53 appears to be crucial when salamanders grow a blastema to regrow a leg. The flip side is that the same suppression features in cancer stem cells, so p53 marks the boundary between useful stem cells and dangerous ones.
Everyday life touches p53 too. Ultraviolet light activates it, setting off processes that lead to melanin production and a suntan. And its evolutionary history is surprisingly recent: modern humans carry more than 1,000 mutated variants, most apparently arising within just the last 5,000 to 10,000 years, while some Neanderthal populations lacked the harmful ones.
Source: P53
