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Solution structure of an oncogenic DNA duplex containing a G.A mismatch
C Carbonnaux1, G A van der Marel, J H van Boom
1Département de Biologie Cellulaire et Moléculaire, Centre d'Etudes Nucléaires de Saclay, Gif-sur-Yvette, France.
Biochemistry
|June 4, 1991
Summary
This study reveals that a G.A mismatch in the K-ras gene DNA duplex changes structure with pH. This pH-dependent structural shift may explain why G.A errors in this oncogenic sequence are poorly repaired.
Area of Science:
- Molecular Biology
- Biochemistry
- Genetics
Background:
- The K-ras gene is a critical oncogene, and mutations within it are common in various cancers.
- G.A mismatches are a type of DNA error that can lead to mutations if not properly repaired.
Purpose of the Study:
- To investigate the structural dynamics of a G.A mismatch within a K-ras gene sequence.
- To understand the pH-dependent behavior of this specific DNA mismatch.
Main Methods:
- One-dimensional and two-dimensional Nuclear Magnetic Resonance (NMR) techniques were employed.
- Analysis of Nuclear Overhauser Effects (NOEs) for nonexchangeable protons.
- Study of exchangeable and A(H2) protons.
Main Results:
- The G.A mismatch is intrahelical across a wide pH range.
- A structural transition occurs around pH 6.0, altering the base pairing and conformation.
- At low pH, G.A forms a specific hydrogen-bonded structure with G in a syn conformation.
- At neutral pH, G.A adopts an anti conformation, shifting to a slipped structure with bifurcated hydrogen bonds.
Conclusions:
- The pH-dependent structural changes of the G.A mismatch in the K-ras sequence are characterized.
- The observed structural shift from a classical to a slipped mispair may contribute to the poor repair of G.A errors in this oncogenic context.