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The Oncologist-2001-Goodsell-298-9 The Molecular perspective Ultraviolet light and pyrimidine Dimers

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The
Oncologist
Fundamentals of Cancer Medicine
The Molecular Perspective:
Ultraviolet Light and Pyrimidine Dimers
DAVID S. GOODSELL
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).
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 2 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.
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:
[email protected] www: http://www.scripps.edu/pub/goodsell ©AlphaMed Press 1083-7159/2001/$5.00/0
The Oncologist 2001;6:298-299 www.TheOncologist.com
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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 UVmodified 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. 1). 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.
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
Goodsell
299
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
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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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!