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The Oncologist, Vol. 6, No. 3, 298-299, June 2001
© 2001 AlphaMed Press

FUNDAMENTALS OF CANCER MEDICINE

The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers

David S. Goodsell

Correspondence: David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu www: http://www.scripps.edu/pub/goodsell

Everyday, we are subjected to a powerful carcinogen as we go about our daily activities. Whenever we walk in the sun, ultraviolet light (UV) attacks our DNA, making chemical changes that corrupt our genetic information. Fortunately, the most dangerous UV light never reaches us at all: the ozone in the upper atmosphere absorbs (at least for now) the energetic UVC wavelengths. The longer UV wavelengths, however, do pass through the atmosphere and fall on us. The UVA wavelengths bordering on visible light, which are often used in tanning booths, are not energetic enough to modify DNA bases (although UVA may play an important role in formation of carcinogenic oxygen radicals). However, wavelengths in the intermediate UVB region are long enough to pass through the ozone but still energetic enough to attack DNA.

Ultraviolet light is absorbed by a double bond in pyrimidine bases (such as thymine and cytosine in DNA), opening the bond and allowing it to react with neighboring molecules. If it is next to a second pyrimidine base, the UV-modified base forms direct covalent bonds with it. The most common reaction forms two new bonds between the neighboring bases, forming a tight four-membered ring (Fig. 1Go). Other times, a single bond forms between two carbon atoms on the rings, forming a "6-4 photoproduct." These reactions are quite common: each cell in the skin might experience 50-100 reactions during every second of sunlight exposure.



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  		Figure 1. Pyrimidine dimer in DNA. A TT dimer (in violet) is shown within a DNA double helix. Notice the four-membered cyclobutane ring formed between the two thymine bases. The dimer causes local distortions in the helix, weakening the interaction with the paired adenine bases and kinking the backbone slightly. The coordinates were taken from entry 1ttd at the Protein Data Bank (http://www.pdb.org).

 
Fortunately, most of these genetic lesions are corrected seconds after they are created, before they can do permanent damage. Our cells use a process known as "nucleotide excision repair" to identify and remove ultraviolet damage. Dozens of proteins work together to seek out corrupted bases, unwind the local DNA double helix and clip out a segment of about 30 bases around the damage. The normal DNA replication machinery then fills the gap, restoring the DNA to its proper form. Nucleotide excision repair is our sole defense against ultraviolet damage, but other organisms have backup defenses. For instance, the endonuclease shown in Figure 2Go simply clips out the damaged base. The placental mammals have lost these additional defenses, perhaps an evolutionary legacy inherited from the earliest nocturnal mammals, which were seldom subjected to the dangers of ultraviolet light. Even today, many rodents show weakened nucleotide excision repair mechanisms.



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  		Figure 2. Recognition of a pyrimidine dimer. DNA repair proteins are not gentle with the DNA that they correct. The endonuclease V from T4 bacteriophage is shown here in green, as it binds to a short stretch of DNA with a TT dimer. The dimer is shown in violet. Surprisingly, the enzyme does not appear to recognize the dimer itself. Instead, it recognizes the weakening of the helix by the dimer: the enzyme kinks the DNA at the site of the lesion and also flips one of the adenine bases away from the dimer and into a pocket in the protein (seen pointing to the left of the DNA strand). Coordinates were taken from entry 1vas from the Protein Data Bank.

 
If the damage goes uncorrected, the genetic information may be permanently mutated. Many times, these dimers cause no problems because they are still read correctly. For instance, TT dimers are often paired properly with adenine bases when replicated. However, this is not always the case. The signature mutation caused by ultraviolet light is a CC to TT mutation, caused when a CC dimer is mispaired with two adenine bases during replication. Because of these mutations, the connection between ultraviolet damage to DNA and cancer is quite clear. These CC to TT mutations often show up in the p53 tumor suppressor gene in skin cancers, compromising its watchdog function. Something to think about next time you are choosing the SPF of your sunscreen!


   ADDITIONAL READING
Top
 Additional Reading
 

  • Black HS, deGruijl FR, Forbes PD et al. Photocarcinogenesis: an overview. J Photochem Photobiol B 1997;40:29-47.
  • Freeman SE, Hacham H, Gange RW et al. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light. Proc Natl Acad Sci USA 1989;86:5605-5609.
  • Lindahl T, Wood RD. Quality control by DNA repair. Science 1999;286:1897-1905.




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