Setting the telomere clock

Telomere length is similar in cloned and naturally conceived animals.

Telomeres, which cap the ends of chromosomes, get shorter with age.They are a kind of molecular clock linked to ageing, cancer, and possibly problems associated with cloning mammals. They get shorter because standard DNA copying machinery tends to stop short of the very end of the telomere, leading to a loss of telomere length with every cell division. Researchers in Germany have now pinned down the exact time during embryo development when the enzyme telomerase (which is absent for the rest of an animal’s life) adjusts embryonal telomeres to the correct starting length.

Groups led by Heiner Niemann at the Federal Agricultural Research Centre in Neustadt, and Lenhard Rudolph at the Hannover Medical School, analysed telomere lengths in various developmental stages of cattle, using cloned embryos as well as IVF and naturally conceived animals. They found that, regardless of the way the embryos originated, the typical embryonal telomere length is adjusted at the transition from the morula (four to 16 cells) to the blastocyst stage. ¹ This transition is a key event in early development, as it involves the first separation into two different kinds of cells: the inner cell mass (from which the embryo develops) and the surrounding trophoblast (which will become the placenta). Analysis in one- to two-year-old cattle confirmed that telomere length in cloned and naturally conceived animals is similar.

In order to generalise the findings, the researchers performed similar investigations on mice, and obtained corresponding results. Additionally, the existence of telomerase knockout mice enabled them to confirm that it is indeed the activity of this enzyme that is responsible for the restoration of telomere length. In the absence of telomerase, no elongation occurs.

While this research has answered a key question, many other factors that influence the gradual erosion and sudden restoration of chromosome ends remain to be elucidated. Michael McEachern at the University of Georgia, Athens, in collaboration with investigators at Tel Aviv University, Israel, has demonstrated just how much of the picture may still be missing. ² These researchers systematically trawled the yeast genome to identify genes that influence telomere length. They found over 150 candidate genes that had not been linked to telomeres before. In two thirds of the mutants, the telomeres were shortened, while in the remaining third, they were longer than expected.

Yeast models have in the past served as useful models of mammalian telomerases (which are extremely elusive because they only occur in minute quantities in early development). These findings suggest, therefore, that human telomerase, too, may have regulatory links to various other parts of the proteome. Cloning issues aside, the erosion of chromosome ends is believed to contribute to ageing, but also to protect against cancer. Which are very good reasons to find out in which ways exactly telomerase interacts with the human proteome.

Michael Gross