Here at the Institute of Cancer Research, London, we’ve long been leaders in the field of discovering genes that are associated with cancer. The latest of many studies that find these links was published this week, finding associations between four gene variants and the common blood cancer multiple myeloma. One of the genes highlighted in that research was TERC, which we briefly described as having been implicated in the ageing process. But I thought the fascinating process that TERC is a part of would be worth looking at in a bit more detail.
TERC is a component of a molecular machine called telomerase, whose job is to maintain DNA caps on the ends of chromosomes. These caps, called telomeres, are vital for protecting chromosomes from damage.
In the absence of telomeres, the bare ends of chromosomes would be indistinguishable from damaged DNA that has snapped into two pieces. Such DNA damage — called “double strand breaks”, because they occur when the double helix is completely severed — is a regular enough occurrence that our cells have a system for repairing it. Without telomeres to cap them, this system would mistake the bare ends of chromosomes for DNA damage, and would go around incorrectly glueing them together, creating all sorts of problems — as we’ll see later.
But telomeres are more sophisticated devices than mere caps on the chromosomes. They play an important role in regulating cell proliferation. Every time a cell divides into two, its genome must be reproduced, and the machinery that makes these copies attaches to the telomere before working its way along the chromosome duplicating the double helix. But crucially, it can’t copy the very tip of the telomere where it first attaches, meaning that every time cell division occurs, telomeres get that little bit shorter.
Telomeres in effect provide the cell with a simple memory in which is stored a count of how many times it has been through the cell division process in the past. Eventually, when the telomeres have become short enough, they signal to the cell that they’ve had enough: it’s time for the cell to settle down and give up its hopes of dividing any further.
This fixed number of cell divisions is known as the “Hayflick limit” after Leonard Hayflick, who noted the phenomenon in 1961. Because cancer cells proliferate rapidly, going through many rounds of cell division, this cellular mortality mechanism is one of our many built-in defences against the disease. But sometimes devious rogue cells discover ways around the barrier: either they can keep resetting the clock, or they can just ignore its signal to stop dividing.
The fountain of youth is a poisoned spring
The ability to reset the telomere clock is an important piece of functionality that some cells really need. It’s vital early on in development, for example, when we have to make our way from a single fertilised egg cell to the trillions of cells of a grown person. And it’s needed by the stem cells that replenish our stocks of those cells that have a short life and fast turnover – some immune cells, for example.
This is where telomerase — and our gene TERC – come in. Telomerase is active in controlled quantities in those cells, extending the telomeres back to their starting length.
We talked about TERC as a gene that “helps control the ageing process” because telomerase has been proposed as a potential anti-ageing mechanism. One effect of the Hayflick limit is that cells stop dividing, settle down, and over time naturally die out. Eventually we start to run out of healthy cells, and this manifests itself in many of the signs of ageing.
But it’s this ageing mechanism that forms part of our defence against cancer. As our team say in their report on the genes associated with myeloma this week, telomerase activation is a feature of myeloma, and carriers of the TERC variant tend to have significantly elongated telomeres. We’ve known for some time that this cellular ageing process tends to be disrupted in most cancers, not just myeloma.
Evading Hayflick’s limit: the chromosomal chaos of cancer
Activating telomerase isn’t the only way for cancers to beat the clock on cell division. The other way is to ignore the Hayflick limit altogether: to just go on dividing, long after the telomeres have run out. Any number of mutations to a whole suite of genes could do this, by knocking out the systems that tell cells to stop dividing and to self-destruct in response to serious damage.
When this happens, cells go on dividing, and each time they reproduce their genomes, their chromosomes continue to get that little bit shorter. With chromosomes left uncapped with telomeres, the DNA double-strand break system will be erroneously activated. Loose ends of different chromosomes get stuck together, but the resulting mega-chromosomes are very unstable, and liable to be ripped apart during the next cell division. Soon the genome in these cells descends into the chromosomal chaos that is characteristic of advanced cancers, as fragments of chromosomes are rearranged, moved around, and stuck back together, sometimes in the process creating Frankenstein fusion genes with strange new behaviours.
There will always be those who dream of sidestepping the ageing process, perhaps by manipulating the way telomeres are maintained, or the signals they trigger. But that would be a dangerous game, judging by our research into the roles of genes like TERC – because the same system responsible for our wrinkles also seems to protect us from cancer.