The principles governing the replication fidelity of genomes are not fully
understood yet. Watson and Crickís base-pairing principle
for matched deoxyribonucleotide (DNA) bases can explain why the guanine-cytosine
and adenine-thymine base pairs are approximately one hundred times more
stable thermodynamically than mismatched combinations. In vitro, DNA polymerases
reduce the number of mismatched base pairs to about 10-6
per Watson-Crick base pair. Replication fidelity can further be enhanced
to a mutation probability of 10-10 or less
in vivo if optimal conditions for DNA synthesis are provided by polymerase-assisting
proteins and DNA-repairing enzymes. The precise reasons for the formation
of mismatched base pairs (mispairs), which are responsible for a substantial
part of DNA mutations, are still in debate. Although it is agreed that
a template-directed "reading" of the hydrogen-substitution pattern in the
heterocyclic bases is crucial for proper base pairing during DNA synthesis,
it is not clear which type of "misreading" leads to mispairs. Misreading
may be due to a non-Watson-Crick base pairing as well as to a change in
the hydrogen substitution pattern, leading to Watson-Crick-like mispairs.
The surprising discovery of the selective and quantitative DNA-polymerase-catalyzed
formation of a pyridine-pyrimidine base pair (involving a nucleotide base
analogue) indicated that rare tautomeric forms in the template DNA strands
can lead to Watson-Crick-like mispairings that are hardly recognized by
the polymeraseís proofreading activity. This reveals new pathways for substitution
mutations (replication-dependent DNA point mutations) and suggests a new
type of mutagen in vivo.
Review with 131 refs. on nucleoside base pairing and mismatches in base
pairing. The prepn. of nucleoside and nucleotide analogs, and of oligonucleotides
by both liq. and solid-phase methods are discussed, as well as base-pairing
with modified nucleotides.
Figure: a) Reading frame of ionised nucleobases; b) reading frame
of tautomeric nucleobases; c) reading frame of wobble-shifted nucleobases;
d) reading frame of Hoogsteen-faced nucleobases. A: hydrogen bond acceptor;
D: hydrogen bond donor.
