TY - JOUR
T1 - Elevated mutant frequencies and predominance of G:C to A:T transition mutations in Msh6−/− small intestinal epithelium
AU - Mark, Sean C.
AU - Sandercock, Linda E.
AU - Luchman, H. Artee
AU - Baross, Agnes
AU - Edelmann, Winfried
AU - Jirik, Frank R.
N1 - Funding Information:
We are grateful to S Lines for maintaining the animal colony and help in genotyping. This study was supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society (to FR Jirik), and by the Alberta Heritage Foundation for Medical Research (AHFMR) (to FR Jirik) and NIH grant number CA 76329 (to W Edelmann). FR Jirik was the recipient of AHFMR Scientist and Canada Research Chair awards.
PY - 2002
Y1 - 2002
N2 - 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 on these heterodimers is derived from in vitro studies, it was of interest to study the in vivo consequences of a lack of MutSα. To this end, Big Blue™ mice, that carry a lacI+ transgenic λ. shuttlephage 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 lacI gene mutation spectrum was dominated by G:C to A:T transitions, highlighting the critical importance of the MutSα complex in suppressing this frequently observed type of spontaneous mutation.
AB - 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 on these heterodimers is derived from in vitro studies, it was of interest to study the in vivo consequences of a lack of MutSα. To this end, Big Blue™ mice, that carry a lacI+ transgenic λ. shuttlephage 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 lacI gene mutation spectrum was dominated by G:C to A:T transitions, highlighting the critical importance of the MutSα complex in suppressing this frequently observed type of spontaneous mutation.
KW - Big Blue™
KW - DNA mismatch repair
KW - LacI
KW - Msh6
KW - Small intestinal epithelium
KW - Transgenic shuttle-phage
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U2 - 10.1038/sj.onc.1205861
DO - 10.1038/sj.onc.1205861
M3 - Article
C2 - 12370835
AN - SCOPUS:0037057327
SN - 0950-9232
VL - 21
SP - 7126
EP - 7130
JO - Oncogene
JF - Oncogene
IS - 46
ER -