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The Response of the Eukaryotic Replisome to G-quadruplex- and i-motif-forming Sequences

DNA replication is a tightly regulated, complex process that ensures the entire genome is inherited accurately in each cell division. Secondary DNA structures such as G-quadruplexes (G4s) and intercalated-Motifs (i-motifs) can pose a challenge to the replication machinery and in turn threaten genome stability. Multiple lines of evidence suggest G4s interfere with replication, but the underlying mechanism remains unclear. Moreover, there is a lack of evidence of how i-motifs affect the replisome. Here, we have reconstituted replication of physiologically derived structure-forming sequences and found that a single G4 or i-motif is sufficient to arrest DNA replication. This ability to stall replication correlates with the stability of the secondary structure under physiological conditions. Both G4s and i-motifs trigger-helicase polymerase uncoupling, which can only be rescued by a specialised helicase, Pif1. This study provides a potential mechanism for quadruplex structure formation and resolution during replication and highlights G4s and i-motifs as endogenous sources of replication stress, which may explain their genomic instability and mutation frequencies in cancer.