Work

Controlling Topology of a Telomeric G‐quadruplex DNA With a Chemical Cross‐link

Year: 2025

Type: article

Abstract: DNA G‐quadruplexes (G4s) are noncanonical structures formed in guanine‐rich sequences. Within the human genome, they are nonrandomly distributed and influence DNA replication, gene expression, and genome maintenance. Numerous proteins involved in these processes have been identified as G4‐binding proteins. However, the interaction of proteins with G4s in the context of double‐stranded DNA in vitro has been difficult to study due to the transient nature of G4s in the presence of complementary DNA. To overcome this challenge, introducing internal covalent cross‐links between distant nucleotides within the DNA sequence may promote pre‐folding of G4 structures, thereby shifting the thermodynamic equilibrium toward G4‐formation. We used a Cu(I)‐catalyzed azide–alkyne cycloaddition to create a cross‐link between 2′‐ O ‐propargylguanosine and N 6 ‐azidoethyl‐2′‐deoxyadenosine in the DNA telomeric sequence (TAG 3 T) 2 . A cross‐link between G3 and A8 reinforced the parallel G4 topology that was stable in the presence of complementary DNA. Moreover, even in the presence of its complementary strand, this cross‐linked G4 recruited the parent native DNA (TAG 3 T) 2 to form a hybrid G4. These results suggest that cross‐linking provides a useful tool for stabilizing noncanonical DNA structures in the presence of complementary strands, enabling their study within the context of genomic DNA.

Source: Chemistry - A European Journal

DOI: 10.1002/chem.202501467

Authors: Bruce Chilton, Patrick J. B. Edwards, Geoffrey B. Jameson, Tracy K. Hale, Vyacheslav V. Filichev

Institution: Massey University

Language: English

Topic: DNA and Nucleic Acid Chemistry

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $4,640

Funders: Massey University, Health Research Council of New Zealand