Molecular Genetics

DNA information can be damaged by mistakes made during replication

Facts

The replicating DNA in the diagram has a mismatched base pair at the 3' end of the lower strand. DNA polymerases vary in their ability to continue elongation at a mismatch. The HIV-1 reverse transcriptase can elongate some kinds of mismatched ends efficiently. E. coli DNA polymerase III and eucaryotic nuclear DNA polymerases are inefficient in such elongation. The pause caused by the inefficiency provides an opportunity for the 3' to 5' exonuclease activity of the DNA polymerases to remove the mismatched base.

Successful "misincorporation" will occur with DNA polymerases of high fidelity when the template base is in the minor tautomeric form or has been otherwise damaged. "Stuttering" of polymerases or "slippage synthesis" sometimes occurs at homo-oligomeric sequences, resulting in bulges in the duplex. Template-product dissociation followed by reassociation at a homologous sequence in a non-homologous position leads to a duplex with an unpaired loop. Failure to repair results in insertions or deletions. This phenomenon is often called copy-choice recombination.

Interpretations

• Copying of E. coli and nuclear genomes occurs with high fidelity.
• Elongation of mismatches in HIV-1 contributes to a high mutation rate.

Further information

• Mutations in DNA polymerases can result in enzymes that misincorporate nucleotides, creating mismatches, and can more readily elongate mismatched ends. These polymerases act as mutator polymerases.
• Mutation rate refers to the probability with which a particular nucleotide undergoes a substitution in a replication cycle. Mutation frequency is often measured instead. This refers to the result of selection, the frequency of substitutions that survive selection in individuals.
• Mismatches can be repaired.

This is page 3124 of Molecular Genetics by Ulrich Melcher, © 1997, 1998, 2000