Interstrand cross-links at T(A/T)4A 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)4A motifs are on average scarce and scattered. However, significantly higher local motif densities were identified in distinct minisatellite regions (200-1000 base pairs of approximately 85-100% AT), herein referred to as "AT islands." 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 (approximately 4.7-7.1 lesions/kilobase pair/microM
drug) in several prominent AT islands, compared with markedly lower lesion levels in several motif-poor loci and in bulk cellular
DNA (approximately 0.8-1.3 and approximately 0.9 lesions/kilobase pair/microM
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 AT-rich non-coding domains can be regarded as a novel class of critical targets for anticancer drugs.