Our genetic material comes in chunks called chromosomes, the ends of which are capped with repetitive DNA sequences called telomeres. Every time DNA is replicated to make new cells bits of the telomeres are lost – so they get shorter – and eventually this turns on a stress signal that puts a stop to further cell reproduction. So, the older you get the shorter your telomeres become and when that stops you making more cells you conk out. Lurking within our chromosomes is a gene that can stop this happening: it encodes an enzyme called, of course, telomerase that extends chromosome caps. But, you exclaim, a well-known feature of cancer cells is that they are ‘immortal’ – so they must find a way of switching on the telomerase gene that in normal cells is turned off to ensure that we don’t hang around too long. And indeed most of them do – which highlights another of life’s balancing acts: telomerase off = finite life-span, telomerase on = cancer.
Putting a cap on it
Human telomeres contain thousands of repeats of the 6-base sequence TTAGGG that cap the ends of chromosomes. To prevent these being worn away and enable cells to become ‘immortal’, the genetic mayhem that characterizes tumours usually includes a means of activating telomerase. However, you won’t be surprised to find that extending telomeres is a complicated business and the telomerase enzyme is just one bit of a multi-component molecular machine that does the job. One of the bits is a protein by the name of POT (POT1 to be precise) and a Spanish group have just shown that mutations in POT1 occur in chronic lymphocytic leukemia. Normal POT1 acts as a negative regulator that suppresses telomere extension: mutations in POT1 permit telomere extension and also enable chromosomes to fuse end-to-end with one another – a common type of genetic damage in leukemia. It appears that, although POT1 mutations are quite rare, they occur only in the clinically aggressive subtype of CLL – so they provide not only a new potential drug target but also a prognostic indicator.
Incidentally, despite what you might think, ‘cancer genes’, i.e. genes that by acting abnormally (as a result of suffering some sort of mutation, either in themselves or indirectly) can help to drive cancer development, have names that are very sensible and logical. Thus POT1 stands for protection of telomere – and it’s POT1 just in case a close rello turns up – which would be POT2.
Ramsay, A.J. et al., (2013). POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nature Genetics 45, 526–530.