Discovery of Telomeres

In 2009 Elizabeth Blackburn together with Carol Greider and Jack Szostak were awarded Nobel Prize in Physiology and Medicine for the discovery of telomeres and the enzyme called telomerase. This is probably the most important recent discovery made in biology because it makes our conception of replication much clear and it completely changed peoples view on aging and mortality. This discovery can now be found in all cell biology textbooks, and I am also studying this currently.

Telomeres are the kind of “caps” at the ends of chromosomes which protect chromosomes in the cells from fusing with each other and from rearranging. If those abnormalities occur then cancer can be developed.

Like all the chromosomes with its genes, telomeres are the sequences of DNA. A chemical code made of four nucleic acids G (guanine), A (adenine), T (thymine), C (cytosine). Blackburn studied Tetrahymena (a freshwater pond), and identified a sequence of DNA that was repeated a few times at the end tips of the chromosomes. The purpose of this identified sequence (CCCCAA) was unclear at the beginning.

Bright fluorescent staining makes telomeric regions visible (light blue tips) on these blue-stained human chromosomes.

Figure 1.

Then she found that it is essential for DNA replication (copying of it). During replication an enzyme called DNA polymerase which duplicates DNA cannot complete duplication all the way to the end of chromosome. Therefore, it was considered that telomeres become shorted and shorted after each replication and when telomere consumed the cell dies. You can think about it like the plastic end tip of the shoelace, when it is broken the shoelace tip becomes sticky and hard to tie.

Then, she noticed that something was adding a new DNA at the ends of the chromosomes. The telomeres were not shortening, and so the cells were able to replicate enormously. They were in a fact “immortal”. This something was found to be telomerase, an enzyme also called telomere terminal transferase. This enzyme adds more repeat sequences to the end of the DNA in germline cells (egg and sperm), thus making them “immortal”. However, somatic cells are “mortal” because of much lower levels of this enzyme activity. When telomeres in somatic cell shorten to critical level, this cell no longer divides. This phenomenon contributes to some of the changes we see in aging.

Here is the video where Elizabeth Blackburn explaining how she made this discovery.

Now, why actually telomeres shorten? This process is called “end replication problem” that occur in eukaryotes (with nucleus) during replication. It is like someone painting flour in a closed room and while he reaches the corner, he cannot paint the corner as he is standing there.

Take a look at this picture.

Figure 2.

When DNA is unzipped and replicates it makes two new strands: leading (5’ to 3’) and lagging (3’ to 5’) strands. The 5' and 3' indicate the carbon numbers in the DNA's sugar backbone made of deoxyribose linked with phosphate groups via phosphodiester bond. The 5' carbon is attached to phosphate group and 3' carbon is attached to hydroxyl group. Because of this DNA has directionality, like DNA polymerase catalyzes addition of nucleotides to 3’ or it only works in 5’ to 3’ end direction.

Leading strand is called so because it is synthesized continuously toward the direction of replication. Lagging strand is called so because it is synthesized discontinuously in short segments called Okazaki fragments. Each Okazaki fragment is synthesized backward the direction of replication, because DNA polymerase can only elongate strand from a free 3' hydroxyl group. This is called backstitching mechanism. There are RNA primers which provide 3'-OH groups at regular intervals along the lagging strand. While leading strand can synthesize new DNA all the way to the end, lagging strand stays short at the end. Even if last one RNA primer was built at the very end of the DNA, it cannot be removed by DNA because there is no 3'-OH group to start synthesizing it. So, DNA’s shorten. This can be clearly seen from this diagram.

Figure 3.

This “end replication problem” is solved by our enzyme telomerase. Telomerase recognizes the telomere tip of repeat sequence. Telomerase have RNA template inside and using it, telomerase elongates the parental strand by adding additional nucleotides. Therefore, the lagging strand is copied completely. Information at the ends of chromosomes is fully conveyed to the new DNA.
Working principle of telomerase can be seen from this picture and video:

Biology is developing so fast today and it is wonderful how such tiny things make such huge breakthroughs in understanding our life.

Reference list:

"Are Telomeres The Key To Aging And Cancer?." Are Telomeres The Key To Aging And Cancer?. http://learn.genetics.utah.edu/content/chromosomes/telomeres/ (accessed October 27, 2014).

Corey, David. "Abstract." National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810624/ (accessed October 28, 2014).

Wikimedia Foundation. "Telomerase." Wikipedia. http://en.wikipedia.org/wiki/Telomerase (accessed October 28, 2014).

Wikimedia Foundation. "Telomere." Wikipedia. http://en.wikipedia.org/wiki/Telomere#Shortening (accessed October 28, 2014).

Wikimedia Foundation. "Okazaki fragments." Wikipedia. http://en.wikipedia.org/wiki/Okazaki_fragments (accessed October 28, 2014).