Cellular Aging: Telomeres

Telomeres are made up of short tandem repeats of a simple DNA sequence and associated proteins. In humans, and all other vertebrates, the telomeric DNA sequence is 5'(TTAGGG)3', oriented towards the end of one DNA strand, with the complimentary sequence 5'(CCCTAA)3' oriented towards the interior of the chromosome. The duplexed telomeric repeats are arranged in tandem and are present in more than a thousand copies at the end of each human chromosome. At the very end of the chromosome there is a single-stranded protrusion of the G-rich strand that extends for twenty or more repeats.

The first protein components of the human telomeric complex were identified in the mid-1990s. These proteins bind to the double-stranded telomeric repeats and are instrumental not only in promoting stability through formation of specialized structures, but also in regulating other aspects of the telomere, such as the number of repeats present. Within five years of identifying the first telomeric protein, TRF1, the number of proteins known to be present at human telomeres had expanded greatly. These included not only those that bound directly to the telomeric repeats, such as TRF1, and a related protein, TRF2, but also interacting proteins that serve to modify telomeric proteins, such as tankyrase, which binds to TRFI and adds to the protein long chains of ADP-ribose (a molecule which affects protein function). Finally, proteins that were previously identified as being involved in DNA repair and recombination have also been localized to telomeres, although the role of these proteins at the telomere remains unclear.

Experiments carried out by the laboratories of Titia de Lange and Jack Griffith in 1999 identified the something special that allows telomeres to impart stability on chromosome ends. These researchers purified telomeres and associated proteins from human and mouse cells and used electron microscopy to directly visualize the structure of mammalian telomeres. Their results demonstrated that the telomere exists as a dosed circular structure, called the telomere loop, or t-loop. The single-stranded DNA protrusion at chromosome ends, in combination with telomeric binding proteins, is critical in promoting the formation of the t-loop. This structure sequesters the naturally occurring ends of the DNA molecule, the telomere, rendering the chromosome Figure 1 Diagram of telomere structure in cells that allow telomeres to cap and stabilize the ends of chomosomes. The single-stranded protrusion invades the double-stranded telomere to create the telomere loop, or t-loop, sequestering the end of the DNA molecule and preventing it from activating the DNA damage-sensing machinery. This process is likely aided by the action of telomeric proteins. SOURCE: Griffith, Jack D. ``Mammalian Telomeres End in a Large Duplex Loop.'' Cell 97 (1999): 503-514. end unreactive and invisible to the DNA damage-sensing machinery.