G-quadruplex DNA suppresses transcription during DNA replication

In eukaryotic cells, although the B-form double helix is the predominant structure of DNA, various non-B-form DNA structures, including G-quadruplex DNA (G4-DNA), are also widely present. For a long time, G4-DNA has been thought to impede DNA replication due to its unique spatial conformation. However, this study demonstrates that S phase G4-DNA accumulation, far from being a passive byproduct, actively functions as a critical safeguard for genomic stability. Contrary to the traditional view of G4-DNA as a replication barrier, its physiological increase during Early S phase minimizes impact on replication itself. Instead, S phase G4-DNA specifically suppresses transcription by stabilizing the negative elongation factor (NELF) complex, thereby preventing transcription-replication conflicts (TRCs) by spatiotemporally segregating transcription and replication. Replication Factor C3 (RFC3), a component of the replication machinery, directly binds and stabilizes G4-DNA to promote its S phase accumulation. Disruption of RFC3 function or G4-DNA unwinding during S phase releases transcriptional suppression, exacerbating TRCs.