Angewandte Chemie International Edition
© WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
For full article and contact information, see Angew. Chem. Int. Ed. 1999, 38 (5), 708 - 711
Sunburn for Genes
Genes that mutate frequently when irradiated
could owe it to an unusual folding of DNA
When cells are irradiated with UV light, the DNA molecule in which human genetic information is stored can be damaged. This can be the first step in the development of skin cancer. However, the radiation damage is often repaired in time by certain 'repair enzymes'. A Swiss team of chemists, working with Thomas Carell of the ETH in Zürich, has discovered that the efficiency of this repair process depends on the way in which the DNA molecule is folded. This could help to explain why some genes - known as "hot spots" - are more frequently subjected to modification than others.
The cause for damage from UV light can be found in the molecular structure of DNA, more specifically in the base thymine, which is one of the four letters of the genetic alphabet. If two adjacent thymine molecules within DNA are irradiated with UV light, they couple to each other. By doing this, they distort the structure of the rest of the DNA molecule and at these points, the genetic information stored in the undamaged parts of the DNA can no longer be read correctly.
Although little is known so far about the role of the repair enzymes, it is thought that they routinely move along the DNA double helix - somewhat like repairmen on a stretch of railroad track. If they find two coupled thymine molecules, they twist these bases out of the helix and cut them apart again. In this way, the DNA strand can once again be 'read' by other enzymes.
This twisting is precisely what can cause problems, conclude the Zürich chemists from their observation of hybrid duplexes of DNA and RNA, in which the researchers selectively built in double thymines. Hybrid duplexes are molecular aggregates in which a strand of DNA and a strand of RNA are paired - they are formed during the reading of genetic information and in the duplication of DNA, and are folded in an "A conformation". These duplexes are repaired more slowly than "normal" DNA; the special way of folding gives the DNA-RNA double helix too little room to twist the double thymine out of the molecule.
The difficult-to-repair "A conformation" does not only occur in DNA-RNA duplexes however, it has also been observed in ordinary DNA. Perhaps these are the locations of the genes that are especially sensitive to UV light.