Telomeres are the specialized structures at the ends of eukaryotic chromosomes.  Like many other fundamental properties of chromosomes, the existence of telomeres was first recognized by genetic experiments using Drosophila, performed by the “Fly Group” led by TH Morgan in the first decades of the 20th Century. The key experiments that recognized telomeres were done by H. J. Muller. Muller was a pioneer of the use of X-rays to produce mutations.  He plotted dose response curves showing the relationship between radiation dosage and number of lethal events, including cytologically visible internal deletions within chromosomes.  A deletion that removes an internal region of a chromosome requires two radiation “hits”, one on each side.  Muller noted that “terminal deletions” – deletions that apparently removed the ends of chromosomes – also followed a two-hit response. This was enigmatic, since it seemed that terminal deletions should require only a single radiation hit that removed end of the chromosome.  He postulated that, although these events were not truly terminal deletions, although they appeared that way as viewed in the microscope; rather some structure at the very ends of the chromosomes was essential and thus was being retained in these deletion events.  These essential structures were termed telomeres (“end pieces”), without any knowledge of their structure or other functions.

What do telomeres do?

Muller’s radiation experiments identified one of the important functions of telomeres: to seal the ends of chromosomes.  The end of a linear molecule such as the DNA in a chromosome is structurally equivalent to a double-stranded break in the molecule.  Double-stranded breaks in DNA occur often, either as part of the normal activities of the cell (such as recombination of DNA sequences) or as damage to the DNA.  Most such breaks are rapidly repaired to protect the integrity of the DNA.  Breaks that are not repaired at all, or that are not repaired rapidly, are subject to a process known as non-homologous end joining, in which the broken ends of DNA molecules are joined together without regard to sequence or origin; chromosome rearrangements like translocations, probably arise through non-homologous end joining of double-stranded breaks on two different chromosomes.

If we can infer a premise underlying a biological function for a moment, the cell connects a broken DNA molecule to something, even if it is not the same DNA molecule, rather than leave it broken.  In fact, if telomeres are removed by a true terminal deletion, the ends of chromosomes do fuse with one another.  Thus, telomeres protect the ends of chromosomes from being treated like another double-stranded break.

The second and more widely recognized function of telomeres is their role in DNA replication. The story goes that this role was recognized by Watson when he was drawing diagrams of DNA replication for his seminal undergraduate textbook The Molecular Biology of the Gene in the early 1970s.  Watson noticed that replication cannot extend to the very ends of the chromosome, what is often called “the end replication problem”. He postulated in his book that telomeres were responsible for the end replication of chromosomes.  Even if this version of the story can’t be easily verified, it is true that his textbook drew attention to the end replication problem.  (Russian geneticist Alexy Olovnikov had reached this same conclusion in 1971, but his work was published in Russian and not widely recognized.)  In the mid-1970s, Elizabeth Blackburn, working in the laboratory of Joseph Gall, one of the most influential cytogeneticists of the past half-century, began working on the structure and replication functions of telomeres.  Most of what is described concerning telomere biology is work done by Blackburn, her then student Carol Greider, and Jack Szostak in the 1980s and early 1990s, all of whom shared a Nobel Prize for this work in 2009.

The role of telomeres in disease

While solving the end replication problem and protecting the ends of chromosomes from unwanted fusions are the key known roles of telomeres, they have also been associated with cellular immortality in cancer cells and germ cells, as well as with aging at the cellular and even organismal levels, known as senescence.  The exact nature of this role is not clear.  Telomerase is not active in most cells of an adult, but it becomes re-activated in tumor cells and is active in germline and rapidly dividing embryonic cells. Thus, in the somatic cells of an adult, telomeres are getting shorter as the cells divide, resulting in an association between the age of a cell (that is, the number of times it has divided) and the length of the telomeres.  As such, it has been widely postulated that the length of the telomere affects or regulates the number of times a cell can divide.

Much work by many scientists over the past two decades has been devoted to understanding the connection between telomere length and cellular immortality and senescence.  After all, if telomere length is a key component for cancer and aging, drugs or therapies that alter telomerase function and telomere length might hold significant medical promise.  To date, no therapies based on telomerase and telomere length have been developed, so the connection remains strong but elusive.  It may be that telomerase function and telomere length are not key for cancer and senescence, but rather that both these are consequences or symptoms of another unknown cellular function or program.

Ironically, the one well-studied organism that seems to lack telomerase and conventional telomere structure is Drosophila melanogaster, the organism in which Muller proposed the existence of telomeres.  In Drosophila, the end replication problem is solved not by telomerase but rather by the addition of certain classes of transposable elements to the ends of chromosomes.  These additional transposable elements have a role analogous to telomerase in extending the normal end of the chromosome to allow replication of the lagging strand, but the mechanism is quite distinct.