G-Quadruplex

Nucleic acid sequences that contain a great deal guanine, are able to form four-stranded structures, which G-quadruplexes, G tetrads, DNA, or G4 may be cited.

Properties

G -quadruplexes are composed of a square array of Guaninmolekülen which are stabilized by hydrogen bonds by forming Hoogsteen base pairs. In addition, they are supported by a monovalent cation, usually potassium, stabilized in the center of the tetrad. They can be produced from DNA, RNA, PNA and LNA, and may thereby be an intramolecular, bimolecular and tetra- molecular, that is, from one to be composed of two or four subunits. Depending on the direction of the strands or strand portions forming the tetrads, which structures are described as being parallel or anti-parallel.

The general sequence of G- quadruplexes is

With any loop NL1- 3 having a length of between one and seven nucleotides.

Quadruplexes are less frequent in exons. At G -quadruplexes bind the RecQ helicase that is causing the Werner syndrome and binds to the Bloom 's syndrome protein. An artificial zinc finger protein named Gq1 was also developed that fits on G -quadruplexes, as well as their specific antibodies.

Cationic porphyrins also bind to G- quadruplexes, as the molecule telomestatin.

Quadruplexes in telomeres

The repetitive DNA sequences of telomeres a variety of organisms form G -quadruplex structures. This could often be shown in vitro ( " in Reaganzglas " ), in some cases, also in vivo ( in living cells). Telomeres in humans and all vertebrates consists of many repeats of the DNA sequence GGTTAG. The quadruplexes formed by this structure have now been well studied by NMR and X-ray structure analysis. The arrangement of these quadruplexes in telomeres appears to reduce the activity of the enzyme telomerase, which is responsible for the maintenance of telomere length and in 85 % of all cancers plays a role. This is an important approach for the development of drugs.

Nichttelomerische quadruplexes

Also increased in recent times, the interest in quadruplexes, which do not occur in telomeres. Responsible for this is the work of Hurley with the proto-oncogene c -Myc, which apparently forms a quadruplex in a region that is hypersensitive to nuclease and which plays an important role in gene activity. Then you found out that many other genes have G -quadruplexes in the promoter regions, this included also the beta -globin gene of the chicken, human ubiquitin ligase RFP2 and the proto-oncogenes c-kit, bcl -2, VEGF, H- ras and N- ras.

Overall studies of genomes to the formation of G- quadruplexes have been conducted which have identified 376,000 Putative quadruplex sequences ( PQS) in the human genome, although probably not all of which occur in vivo so. A similar study Putative G- quadruplex has been discovered in prokaryotes. There are several possible ways quadruplexes could control gene activity, either by down-regulation or up-regulation. One possible model is shown opposite illustrate, this blocked a G -quadruplex in or near a promoter, transcription of the gene, thus this is so disabled. In another model, a quadruplex in the noncoding strand of DNA helps to maintain an open configuration of the encoding DNA, thereby improving the expression of the respective gene.