How are G-quadruplex forming sequences associated with human mitochondrial DNA deletion breakpoints in disease?
['["n this work, we performed a computational analysis of the human mitochondrial genome using the \\"Pattern Finder\\" G-quadruplex (G4) predictor algorithm to assess whether G4-forming sequences reside in close proximity (within 20 base pairs) to known mitochondrial DNA deletion breakpoints.", "Circular dichroism and UV spectral analysis demonstrated that mitochondrial G-rich sequences near deletion breakpoints prevalent in human disease form G-quadruplex DNA structures.", "Direct repeat sequences are not required at the breakpoints of age-associated mitochondrial DNA deletions in rhesus monkeys.", "Most of the analyzed deletion breakpoints showed nucleotide repeats flanking the deletions. ", "Currently, the multiple types of GQ sequences and their association with human mtDNA stability are unknown.<br><b>RESULTS</b>: Here, we show an association between human mtDNA deletion breakpoint locations (sites where DNA ends rejoin after deletion of a section) and sequences with G-quadruplex forming potential (QFP), and establish the ability of selected sequences to form GQ in vitro.", "A biochemical analysis of purified recombinant human Twinkle protein (gene product of c10orf2) showed that the mitochondrial replicative helicase inefficiently unwinds well characterized intermolecular and intramolecular G-quadruplex DNA substrates, as well as a unimolecular G4 substrate derived from a mitochondrial sequence that nests a deletion breakpoint described in human renal cell carcinoma.", "DNA sequences proximal to human mitochondrial DNA deletion breakpoints prevalent in human disease form G-quadruplexes, a class of DNA structures inefficiently unwound by the mitochondrial replicative Twinkle helicase.", "Association of G-quadruplex forming sequences with human mtDNA deletion breakpoints."]']
G-quadruplex forming sequences are associated with human mitochondrial DNA deletion breakpoints in disease by residing in close proximity (within 20 base pairs) to known deletion breakpoints. Circular dichroism and UV spectral analysis have shown that G-rich sequences near deletion breakpoints form G-quadruplex DNA structures. Nucleotide repeats flanking the deletions are also observed at most analyzed deletion breakpoints. The ability of selected sequences to form G-quadruplexes in vitro has been established, and these structures are inefficiently unwound by the mitochondrial replicative Twinkle helicase.
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