Role of carcinogen-modified deoxynucleotide precursors in mutagenesis

Abstract

Agents which damage or modify cellular DNA will generally also modify the nucleotide precursor pools, sometimes preferentially (Topal and Baker, 1982). There are at least two different ways that incorporation of modified (possibly promutagenic) nucleotides could, theoretically, make a significant contribution to the mutations induced by these agents. Modified bases may exhibit ambiguous base pairing and produce mutations during normal replication or they may induce secondary mutations as a result of processing subsequent to incorporation. There are important precedents for such possibilities. Classical studies on mutagenesis with prototype mutagens like 2-aminopurine (2-AP) and 5-bromouracil clearly show that mutations can occur by incorporation of deoxynucleotides of tautomeric or ionized (Sowers et al., 1987) bases into newly synthesized DNA (Ronen, 1979; Lasken and Goodman, 1984, Coulondre and Miller, 1977). 5-Hydroxymethyl-2′-deoxyuridine (HMdU), a product of oxidative DNA damage, can also be (re)incorporated into cellular DNA with both toxic and mutagenic consequences (Kaufman, 1987; Shirname-More et al., 1987). Furthermore, modified nucleotides may alter the pool sizes of the normal nucleotides and indirectly produce toxic and mutagenic effects. However, these effects are generally see at high, nonphysiological, concentrations of the modified precursors and may not be relevant under physiological conditions. The relative importance of modified deoxynucleotide precursors in the production of mutations by alkylating and oxidative DNA-damaging agents is discussed.