Abstract
Evolutionarily retained G‐quadruplex DNA (QDNA) is comprised of Hoogsteen hydrogen bonded guanines that form stable stacked tetrads, which can impede DNA synthesis. QDNA replication is critical to genomic maintenance and stability because the sequences have been conserved in regulatory regions of the genome where they influence transcription and expression of important genes, including tumor suppressors and proto‐oncogenes. Y‐family polymerases (pols) may help bypass these sites. We analyzed the functional activity of the archaeal Y‐family pol Dpo4 against QDNA substrates derived from the c‐MYC promoter. Preliminary extension assays with control non‐QDNA and QDNA substrates demonstrate that Y‐family pols are better able to insert cytosines opposite quadruplex tetrad guanines than Dpo1, a model B‐family pol. Calculated changes in heat capacity (ΔCp°) associated with Y‐family pol‐QDNA complex formation indicate a favorable binding interface, a trend not observed with the model B‐family pol. These results reveal molecular interfaces and functional properties for Y‐family polymerases that are indicative of their suitability for QDNA replication. Supported in part by USPHS R00 GM084460 (R.L.E.).
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