AT-rich Islands in Genomic DNA as a Novel Target for AT-specific DNA-reactive Antitumor Drugs

Jan M. Woynarowski, Alex V. Trevino, Karl A. Rodriguez, Stephen C. Hardies, Craig J. Benham

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Interstrand cross-links at T(A/T)4A sites in cellular DNA are associated with hypercytotoxicity of an anti-cancer 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 ∼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 (∼4.7-7.1 lesions/kilobase pair/μM drug) in several prominent AT islands, compared with markedly lower lesion levels in several motif-poor loci and in bulk cellular DNA (∼0.8-1.3 and ∼0.9 lesions/kilobase pair/μM 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.

Original languageEnglish (US)
Pages (from-to)40555-40566
Number of pages12
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - Nov 2 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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