Levels of Drug/DNA Interactions: A) The first level of interaction is the direct drug interaction with the DNA. Drug binding frequency and sequence preferences are two examples of evaluations of this level. B) The second level involves the disruption of DNA interactions with other molecules that result from the drug/DNA interaction such as DNA/protein interactions. Another possibility (not shown) is the alteration or stabilization of DNA secondary structures. C) The third level is the changes in nuclear activities such as transcription, replication, and repair or disruption in complex ternary structures. Green circles, drug/DNA adduct; black lines, DNA strands, chromosome (with loops); yellow oval, red oval, and pink circle, DNA associated proteins; blue square, protein modification such as phosphorylation or methylation.