Possible mechanisms for the regulation of telomere length.

Since DNA polymerases can only synthesise a new DNA strand in the 5'-3' direction and need a primer that provides a free 3' OH end, the cellular replication machinery is unable to duplicate the 3' ends of linear chromosomes unless special mechanisms are operative. While the telomeres seem to shorten continuously in human somatic cells because of the "end replication" problem, it appears that telomere length is maintained in cancer cells, the germ line and unicellular organisms like yeast and Tetrahymena by a mechanism involving the enzyme telomerase, which elongates the 3' ends of telomeres. However, telomerase must be part of a more complicated mechanism to ensure that there is no net gain or loss of telomeric ends. Here we describe a simple theoretical model that can explain several experimental findings. The simulations show that (i) the proposed mechanism is able to maintain telomeres at a constant length, (ii) this length constancy is independent of the initial telomere length, (iii) mutations of the telomeric sequence lead to an elongation of telomeres, (iv) inhibition of telomerase causes telomeric shortening, and (v) it reproduces and explains the experimental result that the addition of oligonucleotides to the culture medium leads to an increase of telomere length. Copyright 1997 Academic Press Limited