Structure and hydrodynamics of a DNA G-quadruplex with a cytosine bulge

DOI: 10.1093/nar/gky307

Authors: Markus Meier (University of Manitoba) , Aniel Moya-Torres (University of Manitoba) , Natalie J. Krahn (University of Manitoba) , Matthew D. Mcdougall (University of Manitoba) , George L. Orriss (University of Manitoba) , Ewan K. S. Mcrae (University of Manitoba) , Evan P. Booy (University of Manitoba) , Kevin Mceleney (University of Manitoba) , Trushar R. Patel (University of Lethbridge; University of Alberta; University of Calgary) , Sean A. Mckenna (University of Manitoba) , Jörg Stetefeld (University of Manitoba)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nucleic Acids Research , VOL 34

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 16028

Abstract: The identification of four-stranded G-quadruplexes (G4s) has highlighted the fact that DNA has additional spatial organisations at its disposal other than double-stranded helices. Recently, it became clear that the formation of G4s is not limited to the traditional G3+NL1G3+NL2G3+NL3G3+ sequence motif. Instead, the G3 triplets can be interrupted by deoxythymidylate (DNA) or uridylate (RNA) where the base forms a bulge that loops out from the G-quadruplex core. Here, we report the first high-resolution X-ray structure of a unique unimolecular DNA G4 with a cytosine bulge. The G4 forms a dimer that is stacked via its 5′-tetrads. Analytical ultracentrifugation, static light scattering and small angle X-ray scattering confirmed that the G4 adapts a predominantly dimeric structure in solution. We provide a comprehensive comparison of previously published G4 structures containing bulges and report a special γ torsion angle range preferentially populated by the G4 core guanylates adjacent to bulges. Since the penalty for introducing bulges appears to be negligible, it should be possible to functionalize G4s by introducing artificial or modified nucleotides at such positions. The presence of the bulge alters the surface of the DNA, providing an opportunity to develop drugs that can specifically target individual G4s.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 01/05/2018 16:23

Documents:
gky307.pdf

Discipline Tags:

Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)