DNA and Double-Stranded Oligonucleotides - Free-Radical-Induced DNA Damage and Its Repair - page 377

radicals by GSH. The anomerization at C (1 ) in the presence of a thiol observed

on the nucleoside level (Chap. 10.3) is an indication that reaction (38) cannot be
very fast.

′

The reactions that follow the formation of the C (4 ) radical give also rise to prod-

ucts that are connected with the release of unaltered bases (see above). The de-
cay of hydroperoxides may contribute to delayed base release when the sample is
heated, as has been shown with polynucleotides (Chap. 11.2).
Thus, the time dependence of base release is most likely due to differently
labile diamagnetic products that are formed side by side. Some of the damaged
sites require not only considerable time for the release of unaltered bases but
also heating for a prolonged time, and in cells such lesions will remain a target
for the repair system.

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12 . 5
Clustered Lesions
and Damage Amplification Reactions (Tandem Lesions)

Ionizing radiation is deposited in small packages (spurs, tracks). Some of these
consist of quite a number of ionizations, i.e. a number of radicals are formed in
a very small volume (Chap. 2.2). When a spur (track) interacts with DNA a num-
ber of damaged sites might be formed locally (termed “locally multiply damaged
sites” (LMDS); Ward 1985; Ward et al. 1990); bulky lesions or now more conve-
niently “clustered lesions”). The RBE of ionizing radiation increases with the
ionization density of these radiations (Brenner and Ward 1992; Goodhead 1994),
and this increase is interpreted as an increase in the complexity of the damage
due to an increase in the number and size of clustered lesions. An example is
shown in Table 12.10 (see also data in Table 12.24).
Yet this type of damage is not restricted to ionizing radiation, but certain
'radiomimetic' drugs such as BLM and NCS can similarly produce two (or more)
damaged sites in close proximity (Steighner and Povirk 1990; Meschwitz et al.
1992).
First indications for such sites came from the observation that melting/re-
annealing kinetics differed markedly between -irradiated T1 DNA and the

same DNA damaged by mechanical or enzymatic degradation (Martin-Bertram
and Hagen 1979). It has been concluded that in addition to singly-damaged sites
locally denatured sections of DNA must be formed upon

γ

-irradiation (see also

γ