Abstract
HapMap findings reveal surprisingly asymmetric distribution of recombinogenic regions. Short recombinogenic regions (hotspots) are interspersed between large relatively non-recombinogenic regions. This raises the interesting possibility of DNA sequence and/or other cis- elements as determinants of recombination. We hypothesized the involvement of non-canonical sequences that can result in local non-B DNA structures and tested this using the G-quadruplex DNA as a model. G-quadruplex or G4 DNA is a unique form of four-stranded non-B DNA structure that engages certain G-rich sequences, presence of such motifs has been noted within telomeres. In support of this hypothesis, genome-wide computational analyses presented here reveal enrichment of potential G4 (PG4) DNA forming sequences within 25618 human hotspots relative to 9290 coldspots (p<0.0001). Furthermore, co-occurrence of PG4 DNA within several short sequence elements that are associated with recombinogenic regions was found to be significantly more than randomly expected. Interestingly, analyses of more than 50 DNA binding factors revealed that co-occurrence of PG4 DNA with target DNA binding sites of transcription factors c-Rel, NF-kappa B (p50 and p65) and Evi-1 was significantly enriched in recombination-prone regions. These observations support involvement of G4 DNA in recombination, predicting a functional model that is consistent with duplex-strand separation induced by formation of G4 motifs in supercoiled DNA and/or when assisted by other cellular factors.
Highlights
DNA in its double-stranded form (B-DNA conformation) is a critical genetic component for most organisms
We found that potential G4 (PG4) DNA forming sequences were significantly enriched within hotspots, while a control sequence that would not adopt structure was not differentially distributed
We searched for PG4 DNA (with three to five guanine bases in stem and one to seven bases in loop (Methods and Figure 1)) within 25618 hotspots (,303 Mb) and 9290 coldspots (,37 Mb) that were reported by Myers et al [40]
Summary
DNA in its double-stranded form (B-DNA conformation) is a critical genetic component for most organisms. It is central to cellular function that strict control over integrity of the large and complex DNA molecule is maintained under constant challenge from a variety of factors. These include external environmental abuse (like chemicals and radiation) that lead to mutagenesis and changes that are inherent to the doublestranded DNA form itself. A particular form – the G-quadruplex DNA has seen a resurgence of interest due to interesting findings directly relating such structures to gene regulation in prokaryotes [8] and eurkaryotes [9,10].
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