The persistence of DNA adducts is the result, for the most part, of the failure of DNA repair, so that its structure returns to normal without evidence of alteration. The structural alterations that may occur in the DNA molecule as a result of interaction with reactive chemical species or directly with ultraviolet or ionizing radiation are considerable. A number of the more frequently seen structural changes in DNA are schematically represented in Figure 3.15. The reaction with chemical species produces adducts on bases, sugars, and the phosphate backbone. Bifunctional reactive chemicals may also cause the crosslinking of DNA strands through reaction with two opposing bases. Other structural changes, such as the pyrimidine dimer formation, are specific for ultraviolet radiation (see below), whereas double-strand DNA breaks are most commonly seen with ionizing radiation (see below). On the other hand, most of the remaining lesions demonstrated in Figure 3.15 may occur as a result of either chemical or radiation effects on the DNA molecule. In order to cope with so many structurally different types of DNA damage, a variety of mechanisms have evolved in living cells to deal with each of the types of damage shown in Figure 3.15. A summary of the types of DNA repair most commonly encountered in mammalian systems is given in Table 3.4.
Two types of damage-response pathways exist: one is the repair pathway and the other is a tolerance mechanism (Friedberg, 1994). In repair mechanisms, the DNA damage is removed, £
while tolerance mechanisms circumvent the damage without fixing it. Tolerance mechanisms are by definition error-prone. Certain repair mechanisms reverse the DNA damage; for example, by removal of adducts from bases and insertion of bases into AP sites. One example of direct reversal is the removal of small alkyl groups from the O6 portion of guanine by alkyltransferases. 8
Alkyltransferases directly transfer the alkyl (methyl or ethyl) group from the DNA base guanine to a cysteine acceptor site in the alkyltransferase protein (Pegg and Byers, 1992). In microorganisms, the intracellular concentration of the alkyltransferase protein is regulated by environmental factors, including the presence of the alkylating agents themselves. A similar adaptation may occur in certain mammalian tissues in response to DNA-damaging agents as well as treatments
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