Cellular Aging: Telomeres

In order for a cell to divide and create two equal daughter cells, the chromosomes must be replicated. Telomeres represent a unique challenge to the cell with respect to replication. Eukaryotic DNA replication occurs unidirectionally on each template strand. The enzymes that synthesize DNA, polymerases, require short RNA molecules to act as primers for new strand synthesis, and synthesis occurs in one direction only. Following extension, the primer is removed and the resulting gap filled in. This works well for most of the chromosome, but a problem arises at the very end of the chromosome. Upon removal of the final primer from the daughter strand, a gap remains that can not be replicated. This, in turn, would result in gradual loss of DNA from the chromosome ends each time the chromosome is replicated, and thus at each cell division. The inability of conventional cellular machinery to replicate the ends of DNA molecules came to be known as the end-replication problem. However, it was apparent that a mechanism for replicating chromosome ends existed, because chromosomes are faithfully transmitted to progeny.

Elizabeth Blackburn and Carol Greider first identified the enzyme responsible for telomere replication in a unicellular protozoan, Tetrahymena thermophila. This enzyme, called telomerase, is minimally composed of an RNA molecule and a protein subunit. The RNA molecule, in humans called hTER—for human telomerase RNA, acts as a template to allow the addition of nucleotides to the end of the chromosome. The extension reaction is catalyzed by the protein component, in humans called hTERT—for human telomerase reverse transcriptase. Thus, loss of telomeric DNA due to the end-replication problem may be balanced by an addition of telomeric repeats by telomerase. Telomerase is active in the germ line (the egg and sperm), where it acts to polish off the replication of chromosome ends so that each generation begins life with chromosomes similar to their parents. However, telomerase is not active in most cells of the body, with the result that DNA is gradually lost from the ends of our chromosomes each time a cell divides.