Repetitive Sequences Within Human PKD1 Adopt G‐quadruplex Structures

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by the loss of PKD1 expression, leading to the formation of cysts and lethal kidney disease. Human PKD1 appears to be prone to inactivating mutagenesis, but the mechanisms are undefined. Interestingly, murine PKD1 is comparatively stable, and ADPKD does not naturally occur in mice. We have identified extensive guanine quadruplex repeats in human, but not murine, PKD1 . Guanine quadruplex (G4) DNA is a four stranded structure that forms from patterns of tandem guanine repeats. It has been identified in gene regulatory domains and is a functional partner with oncogenic rearrangements. The abundance of G4 sequence motifs in human PKD1 implicates G4 structure formation in the mechanism of PKD1 mutagenesis. Therefore, we examined the ability of G4 sequences encoded by PKD1 to adopt G4 structures in vitro . Using more than one biophysical approach, we find that sequence repeats within human PKD1 adopt G4 conformations, but only under physiological conditions and when the G4 sequence motifs are present. The repetitive character of human PKD1 also suggests that non‐canonical G4 sequence motifs support G4 DNA structures in vivo , where they increase the potential for mutagenesis and gene inactivation. Since G4 DNA is already connected with site‐specific genetic instability, the formation of this structure within PKD1 may explain how the gene becomes somatically inactivated, leading to ADPKD. Support or Funding Information This research is supported by Western Michigan University Homer Stryker School of Medicine and by the NIH/NIDDK, R15DK119864 to EL