THE KEY TO CHROMOSOME IMMORTALITY: The discovery of telomerase

All of the information needed to direct our development from single cells, our disease susceptibility, the color of eyes and our skin is encoded in our DNA. This vast amount of information is organized in 46 individual chromosomes. Chromosomes consist of linear strands of DNA. As cells divide and our DNA gets replicated, the ends of linear chromosomes cannot themselves get copied. So after multiple cell divisions, the chromosome gets shorter and shorter.
This poses one of the biggest conundrums in biology: as cells divide, how do we safeguard all of the information encoded in our DNA that is so important for our survival? How are genes protected from deletion at the chromosome end? In 1938, Hermann Muller observed that the ends of linear chromosomes had unique properties, and called this region the telomere. In the 1970’s Elizabeth Blackburn and Joseph Gall discovered that all telomeres consisted of a very specific DNA sequence made up of thousands of repeats of the same nucleotides: TTAGGG in yeast, mammals, etc. But what was also curious was that the telomeres differed in length within one organism and even within one cell. The fact that all of these organisms had the same conserved sequence at the ends of chromosomes suggested that the telomere was very important. But if that’s the case then there must be a mechanism to extend the telomere and prevent it from shortening and being deleted after every cell division.
So how does the telomere get established and maintained? This question puzzled scientists in the 1980’s because nothing we knew about biology could explain how DNA could get added onto the end of another piece of DNA. Normal DNA replication by DNA polymerase requires a DNA template so it can’t add anything to the ends of chromosome where there is no template. In the 1980’s this was an important missing piece of biology that was quite a mystery. This puzzle was solved by Elizabeth Blackburn and Carol Greider at the University of California Berkeley and published in their paper titled “Identification of a specific telomere terminal transferase activity in tetrahymena extracts” in Cell in December 1985. Here the two scientists used an interesting organism called Tetrahymena that also has telomeres, however its telomere sequence is a little different: TTGGGG instead of TTAGGG repeats. This organism undergoes a stage in development where it breaks up its DNA into hundreds of small pieces, and each piece of DNA gets its own telomere at both ends. So this was a great system to study how telomeres are established and maintained since it seemed to happen rapidly and synchronously in tetrahymena, unlike in other organisms.
“Specifically these scientists wanted to find out if there was a factor that added telomeres onto DNA in Tetrahymena nuclei” These scientists isolated the nuclei of tetrahymena, which contains all of the DNA and lots of other proteins and factors. We’ll call this the tetrahymena extract. They labeled T or G nucleotides with radioactivity. These nucleotides would be incorporated into newly formed telomeres and radioactively label this new sequence. The scientists mixed the extract, radioactively labeled T and G nucleotides, and a single-stranded DNA template that mimics an already existing telomere in a test tube. Then the scientists looked at the ability of the tetrahymena extract to extend the telomere template. And what do you get? The nuclear extract of tetrahymena when mixed with radioactively labeled T or G nucleotides is sufficient to produce a telomere.
If either of the nucleotides were missing, telomeres couldn’t be produced. The newly formed, radioactively labeled telomere was being added to the single-stranded template and it consisted of the same conserved sequence of TTGGGG over and over again. So this important experiment conducted almost 30 years ago is the first evidence that there is something in the nucleus that can add a conserved sequence “TTGGGG” and extend linear chromosomes. By doing multiple rounds of biochemical purification, Elizabeth Blackburn and Carol Greider then went on to show that a single key enzyme is responsible for this.
They called this enzyme telomerase since it produces telomeres. By discovering that telomerase is the enzyme that can extend the protective caps at the ends of chromosomes called the telomere, these scientists solved one of the most important puzzles in biology: how is our DNA being protected from degradation after each cell division? This important discovery was the reason these scientists along with Jack Szostak won the Nobel Prize in Physiology and Medicine in 2009. Telomerase was discovered by scientists interested in learning more about our own biology.
Since the discovery of telomerase, we now know that this enzyme plays many important roles in aging and diseases such as cancer. By extending chromosomes, telomerase can make some cells immortal! And cancer cells use this enzyme to divide essentially indefinitely. It’s captivating to learn that we live our lives between states of telomere extension and shortening and this has important implications for our biology. It’s fascinating to see the basic science question of how DNA is protected through multiple cell divisions lead to the discovery of an enzyme that is now implicated in a growing number of diseases and whose extremely complex biology we’re still trying to unravel 30 years later.

As found on Youtube