Base mismatches and mutagenesis: how important is tautomerism?

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Tautomerism of nucleotides (enol or imino forms) has been proposed as a mechanism for transitional mutations.
• This hypothesis was based on the idea that tautomeric forms do not distort the DNA double helix structure.
• However, emerging structural data challenge this long-held view.

Purpose of the Study:

• To evaluate the role of nucleotide tautomerism in DNA substitution mutations.
• To reconcile conflicting evidence regarding the tautomeric states of mismatched nucleotides during DNA replication and mutation.

Main Methods:

• Analysis of recent structural data on mismatched base pairs.
• Examination of kinetic studies on substrate transition states during enzymatic reactions.
• Comparison of C1'-C1' distances in various base pairing configurations.

Main Results:

• Recent structural data indicate that mismatched nucleotides exist in their normal keto and amino forms, not enol or imino tautomers.
• 'Wobble' and other non-Watson-Crick base pairings exhibit C1'-C1' distances similar to standard pairings.
• Kinetic studies reveal that substrates predominantly adopt their major tautomeric forms in the transition state.

Conclusions:

• The findings suggest that nucleotide tautomerism may not be a significant factor in causing DNA substitution mutations.
• The standard keto and amino forms of nucleotides appear to be the relevant species in DNA replication fidelity and mutation.
• Alternative base pairing and substrate conformation in transition states are key considerations for understanding mutation mechanisms.