Interstrand cross-links at T(A/T) 4 A sites in cellular DNA are associated with hypercytotoxicity of an anticancer drug, bizelesin. Here we evaluated whether these lethal effects reflect targeting critical genomic regions. An in silico analysis of human sequences showed that T(A/T) 4 A motifs are on average scarce and scattered. However, significantly higher local motif densities were identified in distinct minisatellite regions (200 -1000 base pairs of ϳ85-100% AT), herein referred to as "AT

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... lands." Experimentally detected bizelesin lesions agree with these in silico predictions. Actual bizelesin adducts clustered within the model AT island naked DNA, whereas motif-poor sequences were only sparsely adducted. In cancer cells, bizelesin produced high levels of lesions (ϳ4.7-7.1 lesions/kilobase pair/M drug) in several prominent AT islands, compared with markedly lower lesion levels in several motif-poor loci and in bulk cellular DNA (ϳ0.8 -1.3 and ϳ0.9 lesions/kilobase pair/M drug, respectively). The identified AT islands exhibit sequence attributes of matrix attachment regions (MARs), domains that organize DNA loops on the nuclear matrix. The computed "MAR potential" and propensity for supercoiling-induced duplex destabilization (both predictive of strong MARs) correlate with the total number of bizelesin binding sites. Hence, MAR-like ATrich non-coding domains can be regarded as a novel class of critical targets for anticancer drugs. Cellular DNA is not a uniform target for DNA-reactive drugs. At the nucleotide level, drugs recognize and bind short motif(s) of a few base pairs. The location of drug adducts at the genomic level, however, depends on how these short motifs are