Nucleic acids and chromatin
Nucleic acids and chromatin

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Quadruplex structures

The ends of linear chromosomes are protected from potential damage by special elements called telomeres. In many organisms, telomeres consist of long stretches of DNA that contain many thousands of copies of G-rich repeat sequences. They are easily detected by FISH (Subsection 2.4), as shown in the case of human telomeres in Figure 16. Our attention here is on the unusual DNA structure believed to be formed by a section of these G-rich DNA elements.

Most of a stretch of telomeric DNA is in the form of a double-stranded helix, but the terminal repeats are usually found as single-stranded DNA. In vitro, telomeric DNA has the ability to spontaneously undergo an intramolecular rearrangement and form a higher-ordered DNA called quadruplex DNA, as shown in Figure 17. This type of structure is termed an intramolecular quadruplex as it is formed from a single strand of DNA, the structure being held by the formation of Hoogsteen bonds between a tetrad of four guanine bases in a square planar formation (Figure 17a) and also referred to as a G4 quadruplex.

Figure 16
Figure 16 FISH detection of telomeres in metaphase human chromosomes (obtained from a lymphocyte), using a telomeric DNA probe. In this image, the telomeres light up yellow, whereas the rest of the chromosome is shown in blue.

Several different conformations have been identified in in vitro studies, as shown in Figure 17b. The existence of quadruplex DNA in vivo has been inferred because many proteins have been identified that can bind selectively to quadruplex DNA. These binding proteins include DNA helicases, which have a role in the uncoiling of the DNA helix during replication and repair. Besides the telomeres, the eukaryotic genome possesses other regions that have the potential to fold into quadruplex structures, including the promoter and regulatory regions of many genes. G4 quadruplex structures have also been described in various mRNAs within mammalian cells, these forming characteristic structures that are recognised by RNA binding proteins. An example is shown in Figure 17c.

Figure 17
Figure 17 (a) A quadruplex DNA is predicted to form in the single-stranded G-rich regions of eukaryotic telomeres due to Hoogsteen interactions between four guanines. (b) Three possible secondary structures for quadruplex DNA. (c) An example of a G4 quadruplex structure found in mRNAs. This structure is recognised by an RNA binding protein known as FMRP, which binds to hundreds of mRNAs in the mouse brain.

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