How cells sense the lengths of their telomeres
Shantanu Chowdhury, Indian Institute of Genomics and Integrated Biology, New Delhi
Back in the 1930s, scientists described structures at the ends of chromosomes resembling the protective tape wrapped around the ends of shoelaces. They dubbed them “telomeres”. We’ve subsequently learned that they play an important role in limiting the growing lifetimes of cells; with each cell division, the telomeres shrink until they reach a threshold point whereby cell division ceases; this makes them a critical anti-cancer device. But how do cells “know” how much telomere material is still present, and how do they therefore regulate the amount of telomerase activity – this is the enzyme that builds and maintains telomeres. If you had too much, the telomeres would keep growing, not shortening, rendering a cell immortal. Well now, thanks to Shantanu Chowdhury, Indian Institute of Genomics and Integrated Biology, New Delhi, we think we know. It’s complicated, but bear with us: telomeres, it turns out, bind a protein called TRF2, which protects and stabilises the telomere. But this same protein can act as an off switch in front of the telomerase gene. And if you shorten a telomere, you release TRF2 because there are fewer sites for it to bind, so it binds instead at the telomerase gene, dialling down its activity and stopping telomere elongation. Neat isn’t it?!
Shantanu – Telomeres are pieces of DNA that make the ends of our chromosomes. They’re super important because they decide how long we live and how long our cells are healthy. And while it was known that telomeres shorten with age, it was not clear how does that work and why does that work? Where is the master control, if at all one is there, remained a question that we wanted to explore.
Chris – So every time a cell divides, splits in two, the telomeres on the ends of the chromosomes, they get shorter. So therefore, there’s a threshold number of divisions then a cell can go through before the cell should stop dividing because the telomeres become too short?
Shantanu – You’re right. After they reach that short stage, cells perish. And this is a way of cells making way for new cells to come in and old cells getting out of the system. However, in certain situations, this law is broken and telomeres cease to shorten after replication, giving cells an immortal life, which in other words, is a growing tumour.
Chris – So understanding the molecular clockwork that links cell division and the length of these telomeres, that’s pretty important then, isn’t it, for the lifetime of cells, but also the health of cells, viability of cells and them not becoming cancerous?
Shantanu – Yes. So the master controller about how is this brought about? How does a cell know it has shortened enough? How does a cell break the rule and become a supercell in some way and live forever? So while it was commonly understood that there is a particular protein which synthesises telomeres, which, of course, is known as telomerase, name comes from telomeres and the maker of telomeres is called telomerase. In normal cells, it is super important that telomerase is not present. And therefore, once telomeres shorten, after a cell divides, becomes two and then two becomes four. And as telomeres progressively decrease in length, because normal cells have a very low supply of telomerase, telomeres are not synthesised anymore. We surmised or we thought that there must be a link between how long or short your telomeres are and how much telomerase is getting produced. In other words, if telomeres could control the amount of telomerase present, this would fill sort of a gap, because in effect, it will show that how is this game played that, you know, telomeres will shorten to a certain extent and stop or elongate to a certain extent, but not beyond that. So this is something that was noted before, but was not clear at a molecular level, how this works.
Chris – So, to be clear, then, the telomerase enzyme that makes up the telomeres that builds them and makes them longer, is made on a different part of the DNA. And you’re saying, well, there has to be a signal whereby that enzyme’s activity, that protein is turned on or off, according to the length of the telomere. So when it’s short, the enzyme must be off. So you don’t end up making more telomere otherwise your cells would have no stop clock?
Shantanu – Yes, you’re right.
Chris – And what is the signal that shuttles between the two? Do we know what tells the enzyme how long the telomere is?
Shantanu – We found a third factor, which has been shown earlier that it is important for telomeres to have this factor sitting on telomeres to protect telomeres. And it is known as telomere repeat factor 2, TRF2. This molecule has an ability to bind at places far away from telomeres. We latched on to this finding and asked, could this be a player? Because when telomeres shorten, a certain amount of this factor TRF2 is released because number of positions that it has on telomeres has disappeared because of the shortening. On the other hand, when telomeres elongate, more of this factor is required. Now, if we move to the other location from where telomerase is produced, which is distant from telomeres, we could see that the factor TRF2 is a signal. If there is enough amount of TRF2 available in the cell, telomerase, it’s shut down. It is basically a gatekeeper. It keeps the gate locked when it is present.
Chris – I get you. So the telomeres, when they shorten, they’re normally soaking up this TRF2 signal and that keeps it away and keeps it occupied. But if there’s less telomere material there, this is liberated and it goes to other parts of the including the genome that makes the telomerase enzyme that would build telomeres and it turns it off. So it basically locks off the ability to make the telomeres longer?
Shantanu – Yes, yes, it locks off. And therefore, the converse scenario is when telomeres have to elongate, TRF2 is required at the telomere ends and it is lost from the gate of telomerase, including other regions of the genome and telomerase synthesis goes up. You have more of elongation of telomeres and that is how the cell understands telomeres are too short. I have to open up and elongate or I have elongated enough. Now I have to shut it down.
Chris – So if you boost up the levels of this TRF2 signal that normally turns off telomerase, do you see a reduction in the amount of telomerase enzyme and shorter telomeres? And conversely, if you block this, do you see the telomeres getting longer again, like they’re doing cancer?
Shantanu – Yes, we did exactly this experiment. When we decrease TRF2, telomerase goes up and then telomeres elongate. If we artificially add TRF2 to the cell, it goes and locks the gate of telomerase. When telomerase is not produced, the end effect is telomeres do not get synthesized and telomeres keep shortening.