David S. GoodsellThe Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers

doi: 10.1634/theoncologist.6-3-2982001, 6:298-299.The Oncologist

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Everyday, we are subjected to a powerful carcinogen aswe go about our daily activities. Whenever we walk in thesun, ultraviolet light (UV) attacks our DNA, making chem-ical changes that corrupt our genetic information.Fortunately, the most dangerous UV light never reaches usat all: the ozone in the upper atmosphere absorbs (at leastfor now) the energetic UVC wavelengths. The longer UVwavelengths, however, do pass through the atmosphere andfall on us. The UVA wavelengths bordering on visible light,which are often used in tanning booths, are not energeticenough to modify DNA bases (although UVA may play animportant role in formation of carcinogenic oxygen radi-cals). However, wavelengths in the intermediate UVBregion are long enough to pass through the ozone but stillenergetic enough to attack DNA.

Ultraviolet light is absorbed by a double bond in pyrim-idine bases (such as thymine and cytosine in DNA), open-ing the bond and allowing it to react with neighboringmolecules. If it is next to a second pyrimidine base, the UV-modified base forms direct covalent bonds with it. Themost common reaction forms two new bonds between theneighboring bases, forming a tight four-membered ring(Fig. 1). Other times, a single bond forms between two car-bon atoms on the rings, forming a 6-4 photoproduct.These reactions are quite common: each cell in the skinmight experience 50-100 reactions during every second ofsunlight exposure.

Fortunately, most of these genetic lesions are correctedseconds after they are created, before they can do perma-nent damage. Our cells use a process known as nucleotideexcision repair to identify and remove ultraviolet damage.Dozens of proteins work together to seek out corruptedbases, unwind the local DNA double helix and clip out a

segment of about 30 bases around the damage. The normalDNA replication machinery then fills the gap, restoring theDNA to its proper form. Nucleotide excision repair is oursole defense against ultraviolet damage, but other organ-isms have backup defenses. For instance, the endonucleaseshown in Figure 2 simply clips out the damaged base. Theplacental mammals have lost these additional defenses, per-haps an evolutionary legacy inherited from the earliest noc-turnal mammals, which were seldom subjected to thedangers of ultraviolet light. Even today, many rodents showweakened nucleotide excision repair mechanisms.

The Molecular Perspective: Ultraviolet Light and Pyrimidine Dimers

DAVID S. GOODSELL

The Oncologist 2001;6:298-299 www.TheOncologist.com

Correspondence: David S. Goodsell, Ph.D., The Scripps Research Institute, Department of Molecular Biology, 10550North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail:goodsell@scripps.edu www: http://www.scripps.edu/pub/goodsell AlphaMed Press 1083-7159/2001/$5.00/0

Fundamentals of Cancer MedicineTheOncologist

Figure 1. Pyrimidine dimer in DNA. A TT dimer (in violet) isshown within a DNA double helix. Notice the four-memberedcyclobutane ring formed between the two thymine bases. Thedimer causes local distortions in the helix, weakening the interac-tion with the paired adenine bases and kinking the backboneslightly. The coordinates were taken from entry 1ttd at the ProteinData Bank (http://www.pdb.org).

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Goodsell 299

If the damage goes uncorrected, the genetic informationmay be permanently mutated. Many times, these dimerscause no problems because they are still read correctly. Forinstance, TT dimers are often paired properly with adeninebases when replicated. However, this is not always the case.The signature mutation caused by ultraviolet light is a CCto TT mutation, caused when a CC dimer is mispaired withtwo adenine bases during replication. Because of thesemutations, the connection between ultraviolet damage to

DNA and cancer is quite clear. These CCto TT mutations often show up in the p53tumor suppressor gene in skin cancers,compromising its watchdog function.Something to think about next time youare choosing the SPF of your sunscreen!

ADDITIONAL READINGBlack 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 dependenceof pyrimidine dimer formation in DNA of human skin irradi-ated in situ with ultraviolet light. Proc Natl Acad Sci USA1989;86:5605-5609.

Lindahl T, Wood RD. Quality control by DNA repair. Science1999;286:1897-1905.

Figure 2. Recognition of a pyrimidine dimer.DNA repair proteins are not gentle with theDNA that they correct. The endonuclease Vfrom T4 bacteriophage is shown here in green,as it binds to a short stretch of DNA with a TTdimer. The dimer is shown in violet.Surprisingly, the enzyme does not appear torecognize the dimer itself. Instead, it recog-nizes the weakening of the helix by the dimer:the enzyme kinks the DNA at the site of thelesion and also flips one of the adenine basesaway from the dimer and into a pocket in theprotein (seen pointing to the left of the DNAstrand). Coordinates were taken from entry1vas from the Protein Data Bank.

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