Certain DNA sequences in the genome may exist either in the canonical right-handed B-duplex or in alternative non-B conformations, depending on conditions such as transcription, supercoil stress, protein binding, and so on. Analyses of breakpoint junctions at deletions, translocations, and inversions, where the sites of DNA breakage could be determined at the nucleotide level, revealed that most, if not all, of the breaks occurred within, or adjacent to, the predicted non-B conformations. These findings support a model whereby rearrangements are caused by recombination/repair processes between two distinct non-B conformations, which may reside either on the same chromosome or on two distinct chromosomes. This model was applicable to both Escherichia coli and humans, suggesting that the mechanisms involved are highly conserved.

The number of genomic disorders that are explicable in terms of non-B DNA conformation-mediated rearrangement is considerable (approx 30). Most involve recombination within (or between) chromosomal regions enriched in low-copy repeats (LCRs), whereas lymphoid-specific rearrangements depend on the recombination-activated gene (RAG) recombinase. However, considering the diseases associated with triplet repeat expansions, which are also believed to be mediated by non-B conformations, the total number ofpathological conditions is around 50. This number may increase as further investigations are conducted on additional rearrangements.

The history of investigations on DNA conformations that differ from the canonical right-handed B-form, as related to genetic diseases, dates back to the mid-1960s. Early studies with high-molecular-weight DNA polymers of defined repeating nucleotide sequences demonstrated the role of DNA sequence in their properties and conformations (1). Investigations with

From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ

Fig. 1. Non-B DNA conformations involved in rearrangements.

repeating homo-, di-, tri-, and tetranucleotide motifs revealed the important role of DNA sequence in molecular behaviors. At that time, this concept was heretical because numerous prior physical and biochemical investigations with naturally occurring DNA sequences did not enable the realization of the effect of sequence (1). It should be noted that these biochemical/ biophysical studies in the 1960s predated DNA sequencing by at least a decade.

Early studies were followed by a number of innovative discoveries on DNA conformational features in synthetic oligomers, restriction fragments, and recombinant DNAs. The DNA polymorphisms were shown to be a function of sequence, topology (supercoil density), ionic conditions, protein binding, methylation, carcinogen binding, and other factors (2). A number of non-B DNA structures have been discovered, approximately one new conformation every 3 years during the past 35 years, and include triplexes, left-handed DNA, bent DNA, cruci-forms, nodule DNA, flexible and writhed DNA, G4 tetrad (tetraplexes), slipped structures, and sticky DNA (Fig. 1). From the outset, it has been realized (1,2) that these sequence effects probably have profound biological implications, and indeed their role in transcription (3) and in the maintenance of telomere ends (4) has been reviewed recently.

Moreover, in the past few years, dramatic advances in genomics, human genetics, physiology, and DNA structural biology have revealed the role of non-B conformations in the etiology of at least 46 human genetic diseases (Table 1) that involve genomic rearrangements, as well as other types of mutation events (5).

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