title: An Msh2 point mutation uncouples DNA mismatch repair and apoptosis.
abstract: Mutations in the human DNA mismatch repair gene MSH2 are associated with hereditary nonpolyposis colorectal cancer as well as a significant proportion of sporadic colorectal cancer. The inactivation of MSH2 results in the accumulation of somatic mutations in the genome of tumor cells and resistance to the genotoxic effects of a variety of chemotherapeutic agents. Here we show that the DNA repair and DNA damage-induced apoptosis functions of Msh2 can be uncoupled using mice that carry the G674A missense mutation in the conserved ATPase domain. As a consequence, although Msh2(G674A) homozygous mutant mice are highly tumor prone, the onset of tumorigenesis is delayed as compared with Msh2-null mice. In addition, tumors that carry the mutant allele remain responsive to treatment with a chemotherapeutic agent. Our results indicate that Msh2-mediated apoptosis is an important component of tumor suppression and that certain MSH2 missense mutations can cause mismatch repair deficiency while retaining the signaling functions that confer sensitivity to chemotherapeutic agents.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Diana P
authors.initials: DP
authors.lastname: Lin
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Wang
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.forename: Kan
authors.initials: K
authors.lastname: Yang
authors.forename: Elena
authors.initials: E
authors.lastname: Avdievich
authors.forename: Bo
authors.initials: B
authors.lastname: Jin
authors.forename: Uwe
authors.initials: U
authors.lastname: Werling
authors.forename: Tchaiko
authors.initials: T
authors.lastname: Parris
authors.forename: Naoto
authors.initials: N
authors.lastname: Kurihara
authors.forename: Asad
authors.initials: A
authors.lastname: Umar
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Martin
authors.initials: M
authors.lastname: Lipkin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
mesh_terms: D000409:Alanine; D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020137:Base Pair Mismatch / Q000235:genetics; D022202:Chromosomes, Artificial, Bacterial; D002945:Cisplatin / Q000633:toxicity; D003062:Codon / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000502:physiology; D005998:Glycine; D051379:Mice; D051718:MutS Homolog 2 Protein; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D000409:Alanine; D002945:Cisplatin; D005998:Glycine