Non-B DNA Conformations, Genomic Rearrangements, and Human Disease

Abstract

The history of investigations on non-B DNA conformations as related to genetic diseases dates back to the mid-1960s. Studies with high molecular weight DNA polymers of defined repeating nucleotide sequences demonstrated the role of sequence in their properties and conformations (1). Investigations with repeating homo-, di-, tri-, and tetranucleotide repeating motifs revealed the powerful role of sequence in molecular behaviors. At that time, this concept was heretical because numerous prior investigations with naturally occurring DNA sequences masked the effect of sequence (1). It may be noted that these 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 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 for the past 35 years) and include the following: triplexes, left-handed DNA, bent DNA, cruciforms, nodule DNA, flexible and writhed DNA, G4 tetrad (tetraplexes), slipped structures, and sticky DNA (Fig. 1). From the outset, it was 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 recently been reviewed.However, in the past few years dramatic advances from genomics, human genetics, medicine, and DNA structural biology have revealed the role of non-B conformations in the etiology of at least 46 human genetic diseases ( Table I) that involve genomic rearrangements as well as other types of mutation events. Non-B DNA ConformationsSegments of DNA are polymorphic. A large number of simple DNA repeat sequences can exist in at least two conformations. All of these sequences adopt the orthodox right-handed B form, probably for the majority of the time, with Watson-Crick (WC) 1 A⅐T and G⅐C bp. However, at least 10 non-B conformations (5-7) are formed, perhaps transiently, at specific sequence motifs as a function of negative supercoil density, generated in part by transcription, protein binding, and other factors.Non-B DNA structures (Fig.

Accumulation of the FACT complex, as well as histone H3.3, serves as a target marker for somatic hypermutation

“…Another explanation involves the fact that unwinding DNA from nucleosome produces one negative supercoil (31). It is known that excessive negative supercoil behind the transcription elongation complex tends to form irregular DNA structures called non-B DNA (3,32), which is proposed to be the substrate for DNA-cleaving enzymes such as DNA topoisomerase 1 (6). Such cleavage can induce SHM during repair by error-prone polymerases (33).…”

DNA structures at chromosomal translocation sites

“…(34,58) Another example of non-B DNA structures in disease may be the extremely large block of chromosome-specific repetitive sequences (termed low-copy repeats). These blocks constitute a substrate for recurrent rearrangement associated with >40 human genomic diseases and are predicted to adopt non-B DNA conformations of substantial complexity and size.…”

“…(34,58) This interesting observation raises the possibility that a cruciform was the site of breakage due to action by some nuclease or process (e.g. replication).…”

The versatile interactions of p53 with DNA: when flexibility serves specificity

“…Interestingly, formation of a hairpin structure altered the mode of p53 binding, which then exhibited features of a specific interaction, as p53 proteins occupied a clearly defined site that is determined not by its specific sequence but by its location within the DNA structure. 18 Although the physiological relevance of the p53 interaction with (CTG:CAG)n tracts remains to be elucidated, the notorious instability and high recombinogenic potential of trinucleotide repeats (reviewed by Bacolla and Wells 19 ) suggests the possibility that wild-type p53 may be involved in the regulation of (CTG:CAG)n tract stability. Supporting the notion, our results indicate that wild-type p53 proteins can resolve mismatched duplexes that contain multiple T:T or A:A mismatches by inducing local melting of homoduplexes formed by individual CTG or CAG strands.…”

“…Supporting the notion, our results indicate that wild-type p53 proteins can resolve mismatched duplexes that contain multiple T:T or A:A mismatches by inducing local melting of homoduplexes formed by individual CTG or CAG strands. 18 Considering that there is a strong causative relationship between the formation of hairpin structures by CTG:CAG tracts and the occurrence of DNA breakpoints (reviewed by Bacolla and Wells 19 ) one possibility to be considered is that wild-type p53 by binding to nonlinear structures formed by CTG:CAG tracts can prevent re-arrangements that may occur during DNA replication and transcription.…”