| Summary: | The DNA mismatch repair (MMR) system is primarily responsible for purging newly
synthesized DNA of errors incurred during semi-conservative replication. Lesion recognition is
initially carried out by one of two heterodimeric protein complexes, MutSα or MutSβ While the
former, comprised of MSH2 and MSH6, recognizes mispairs as well as short (1-2 nucleotide)
insertions/deletions (IDLs), the latter, made up of MSH2 and MSH3, is primarily responsible for
recognizing 2-6 nucleotide IDLs. As most of the functional information of these heterodimers is
derived from in vitro studies, it was of interest to study the in vivo consequences of a lack of
MutSa. To this end, Big Blue™ mice, that carry a lacI⁺ transgenic λ, shuttle-phage mutational
reporter, were crossed with Msh6 ⁻ mice to evaluate the specific contribution of MutSα to
genome integrity. Consistent with the importance of MutSα in lesion surveillance, small
intestine epithelial cell DNA derived from lacI⁺ Msh6 ⁻ mice exhibited striking increases
(average of 41-fold) in spontaneous mutant frequencies. Furthermore, the lad gene mutation
spectrum was dominated by G:C to A : T transitions, highlighting the critical importance of the
MutSa complex in preventing this frequently observed type of spontaneous mutation.
|
|---|
