Introduction - Free-Radical-Induced DNA Damage and Its Repair - page 2

A series of non-connected facts are difficult to remember. The pre-war German
chemistry textbooks that were still in common use in my student times con-
tained such an agglomeration of facts. In contrast, the mechanistically oriented
Anglo-Saxon textbooks were a pleasure to read. They taught us the underlying
principles into which facts fitted quite smoothly. Ever since, I have had a foible
for mechanisms, the little brother of the 'laws' that physicists enjoy in their pro-
fession. Mechanisms are only concepts, and we should not adhere to them with-
out reservations, otherwise we get trapped by our prejudices. Our unjustified
bias for a certain concept has been brought to the point by the German physicist
and aphorist Georg Christoph Lichtenberg (1742-1799) in his ' Sudelbücher (entry
L 674)': “ Bei den meisten Menschen gründet sich der Unglaube in einer Sache auf
den blinden Glauben in einer anderen ”, that is, “with most people, the disbelief
in something is based upon a blind belief in something else”. The development of
new concepts is a major contribution to progress in science, and work that leads
to mechanistic concepts is presented here with some preference. However, ac-
cording to Alfred Popper , mechanisms or any other concepts in science can never
be proved; they can only be falsified. A mechanism may be called 'accepted' as
long no experiment has been thought of and has been carried out that could fal-
sify the present view. It is hoped that the mechanistic formulations given in this
topic will trigger further research by trying to falsify them and will thus lead to
a much better understanding of free-radical-induced DNA damage and repair.
Mechanistic aspects can only be adequately dealt with when the complexity
of the system is reduced to the essential, and the reader will see that there is a
strong emphasis on DNA model systems such as the free-radical chemistry of
nucleobases, nucleosides and nucleotides. Increasingly, compounds are synthe-
sized, even up to the double-stranded oligonucleotide level, that allow the gener-
ation of a specific radical, e.g., by photolysis. This is an important breakthrough
as far as mechanistic studies are concerned. Yet most of our present knowledge
of the free-radical chemistry of DNA and its model systems has been obtained
by radiation-chemical techniques (induced by attempts to improve radiotherapy
and by radiation protection concerns). Obviously, the reactions of a given radi-
cal does not depend on its mode of generation, and it has been tried throughout
the topic to extract from these data the more general aspects of DNA free-radical
chemistry rather than those particular to radiation-chemical effects. This, of
course, had to lead to a suppression of some very fine radiation-chemical stud-
ies, notably in the area of low-temperature EPR. Moreover, some of the excellent
biochemical studies such as details of the site-specificity of a given free-radical
reaction did not find an adequate discussion. Space just did not permit this.
Some of the different chemistry of DNA as compared to its low-molecular-
weight model compounds is due to the fact that DNA is a polymer, and some
aspects of polymer free-radical chemistry are dealt with in a separate chapter.
The special properties of dsDNA allow hole and electron transfer to trapping
sites. This is an area that attracts very strong attention at present, and the level
of understanding is already very high.
One way of oxidizing selectively the Gua moiety of DNA is the use of inor-
ganic radicals having the right redox potential. A small chapter is devoted to
such free-radical probes.