Disease relevance of Msh2

• In contrast, adenomas from Msh2 deficient Min (Apc+/-Msh2-/-) mice are not usually associated with LOH [1].
• Most of the completely Msh2-deficient mice succumbed to lymphomas at an early age; lymphomagenesis was synergistically enhanced by exposure to ethylnitrosourea [2].
• Mice with a single wild-type Rb allele develop a syndrome of multiple neuroendocrine neoplasia, and inactivation of both alleles of Msh2 gene predisposes mice to gastrointestinal cancer, lymphomas and tumors of the skin that exhibit a mismatch repair defect [3].
• The mutation rate of the herpes simplex virus thymidine kinase 1 (HSV-tk1) gene was unchanged in Msh3-deficient ES cell lines but markedly elevated in Msh2-deficient and Msh3 Msh2 double-mutant cells [4].
• Here we describe the application of the DSS model of chronic colitis to mice with a defect in the Msh2 mismatch repair gene to discern these early events [5].
• In the large intestine, very few adenomas were found in Msh2(-/-) mice (0.13 per mouse) whereas K-ras(V12)/Cre/Msh2(-/-) mice produced 2.70 adenomas per mouse (increased 20-fold, P<0.01) [6].

High impact information on Msh2

• Our data support a model in which expansion in the germ cells arises by gap repair and depends on a complex containing Msh2 [7].
• No female embryonic lethality in mice nullizygous for Msh2 and p53 [8].
• Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatellite instability and a predisposition to tumours [9].
• Msh2-deficient mice display no major abnormalities, but a significant fraction develops lymphomas at an early age [10].
• Msh2-deficient cells have lost mismatch binding and have acquired microsatellite instability, a mutator phenotype, and tolerance to methylating agents [10].

Biological context of Msh2

• Previous nucleotide sequence analyses of switch recombination junctions indicated that the roles of Msh2 and the MutL homologues, Mlh1 and Pms2, differ [11].
• We conclude that loss of either p53 or Msh2 dependent apoptosis does not predict long-term crypt survival in vivo, however genetic status clearly can modulate survival for some agents such as cisplatin [12].
• Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes [13].
• Taken together, the results indicate that in mouse epidermis and cultured keratinocytes, the MMR protein Msh2 plays a role in the UVB-induced S-phase arrest [13].
• Together with the finding of genome instability in the germinal center B cells, these observations support the conclusion, previously reached for Msh2 mice, that MMR-deficient B cells undergoing somatic hypermutation have a short life span [14].

Anatomical context of Msh2

• The frequency of switching is reduced, similarly to that of B cells singly deficient in Msh2 or Mlh1 [11].
• The ability to engage enterocyte apoptosis does not predict long-term crypt survival in p53 and Msh2 deficient mice [12].
• Somatic Apc mutations (5/sample) were observed in the non-neoplastic intestinal mucosa from Apc+/-Msh2-/- mice but not from Min mice, suggesting that Msh2 deficiency is associated with a hypermutable state in the intestinal mucosa from Apc+/-Msh2-/- mice [1].
• Using Msh2 null mice, we demonstrate that this genetic defect renders normal intestinal epithelial cells susceptible to mutation in vivo at the Dlb-1 locus [15].
• Msh2 status modulates both apoptosis and mutation frequency in the murine small intestine [15].

Associations of Msh2 with chemical compounds

• Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment [12].
• Apoptosis and long term enterocyte survival were examined in vivo after exposure to three cytotoxic agents (Cisplatin, Nitrogen Mustard and N-methyl-N-nitrosourea (NMNU/MNU)) within mice either singly or doubly mutant for p53 and Msh2 [12].
• Compared with wild-type mice, Msh2-deficient animals had higher basal levels of mutation and were more sensitive to the mutagenic effects of temozolomide [15].
• To further dissect the role of Msh2 in SHM and CSR, mice with a "knockin" mutation in the Msh2 gene that inactivates the adenosine triphosphatase domain were examined [16].
• To examine the role of the MSH2 mismatch repair protein in hypermutation, Msh2-/- mice were immunized with oxazolone, and B cells were analyzed for mutation in their VkappaOx1 light chain genes [17].

Regulatory relationships of Msh2

• Heterozygosity for p53 promotes microsatellite instability and tumorigenesis on a Msh2 deficient background [18].
• Furthermore, some Msh2 null clones expressed high levels of Rad51 specifically, a critical component of HRR [19].
• We next compared this mutability preference with those in hypermutating Ramos cells and in msh2(-/-)ung(-/-) mice, since both are reduced or deficient in UNG- and/or Msh2-induced mutations and are thus likely to reflect the sequence specificity of the mutator in vivo [20].

Other interactions of Msh2

• Mlh1 can function in antibody class switch recombination independently of Msh2 [11].
• The association of MLH3 with repetitive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family in the maintenance of repeat unit integrity during mammalian meiosis [21].
• Deficiencies in Ung, Msh2, or Msh6 affect SHM and CSR [22].
• This suggests that Msh2 may play a role in repairing activation-induced cytidine deaminase-generated G-U mismatches [16].
• Likewise, the decrease in erythrocyte counts was more prominent in mice with at least one functional Msh2 allele [23].

Analytical, diagnostic and therapeutic context of Msh2

• Role for mismatch repair proteins Msh2, Mlh1, and Pms2 in immunoglobulin class switching shown by sequence analysis of recombination junctions [24].
• Indeed, we show that Msh2 plays a role in the in vivo initiation of apoptosis after treatment with temozolomide, N-methyl-N'-nitro-N-nitrosoguanidine, and cisplatin [15].
• In the hippocampus of Msh2+/- mice, array data, validated by RT-PCR and western blot analysis, showed reduced expression levels of genes for cytochrome c oxidase subunit 2 (CoxII), ATP synthase subunit beta and superoxide dismutase 1 [25].

References