The superhelix structure of long human telomeric DNA has been revealed for the first time by scientists working at the University of Tokyo's Research Center for Advanced Science and Technology1. Yan Xu and colleagues were interested in learning more about the protective structures, or telomeres, present on the ends of chromosomes.

Telomeres are regions of DNA right at the end of the chromosome and are important for genome stability. “Much like the plastic tips on shoe laces, telomeres prevent the long strands of chromosomal DNA from unraveling and protect chromosome ends from being recognized as double-strand breaks,” says Xu. Mammalian telomeric DNA is composed of the repeating TTAGGG nucleotide unit, but the overall structure of these important cellular components is not sufficiently understood.

Fig. 1: Schematic representation of the four linked G-quadruplex structure and AFM image of a length of DNA with telomeres at either end.

Although various human telomeric DNA structures have been proposed, there has been no experimental proof until now. Xu and colleagues used a combination of atomic force microscopy, fluorescent resonance energy transfer and circular dichroism measurements to make images of the telomere ends (Fig. 1). They were able to show that telomeres are wrapped up into a series of structures known as G-quadruplexes, which according to Xu look rather like “skewered dumplings.” An image of four such units was produced from a chain of 96 nucleotides, with 21 nucleotides required for each G-quadruplex.

As DNA is replicated during cell division, small bits of the telomere break off. Over time this leads to aging of the cell. Damaged telomeres are recognized by the cell as double-strand breaks, which can lead to genome instability resulting in cell senescence or apoptosis (cell death). Knowledge of the overall molecular structure of telomeres could lead to the structure-based design of anti-cancer therapies targeting telomeres.

One way that scientists hope to maintain a sufficient length of telomeric DNA is by harnessing nature’s own technique: targeting the enzyme (telomerase) responsible for elongating the telomere. One of the 2009 Nobel prizes was awarded for discovering how chromosomes are protected in this way. However, most studies now focus on developing molecules that target the G-quadruplex itself. The structural information provided by Xu’s research team will be invaluable in this endeavor.