Disease relevance of MSH3

• Loss of MSH3 protein expression is frequent in MLH1-deficient colorectal cancer and is associated with disease progression [1].
• MSH6 and MSH3 are rarely involved in genetic predisposition to nonpolypotic colon cancer [2].
• As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status [1].
• Mismatch repair and microsatellite instability in esophageal cancer cells [3].
• Mismatch repair gene expression defects contribute to microsatellite instability in ovarian carcinoma [4].

Psychiatry related information on MSH3

• The other explicit memory tests and the reaction time test showed no effect with DUP 996 [5].

High impact information on MSH3

• Mismatch repair stabilizes the cellular genome by correcting DNA replication errors and by blocking recombination events between divergent DNA sequences [6].
• Mismatch repair in replication fidelity, genetic recombination, and cancer biology [6].
• This may explain the rarity of MSH6 and absence of MSH3 germline mutations in HNPCC families [7].
• Mismatch repair activity was examined in human cell extracts using an assay that does not require DNA repair synthesis [8].
• Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability [9].

Chemical compound and disease context of MSH3

• In renal cancer cell lines demethylation with 5-aza-2'-deoxycytidine did not affect the expression of hMLH1 and hMSH3 genes [10].
• Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer [11].

Biological context of MSH3

• Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher's exact test, P < 0.001) [1].
• In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2 [1].
• Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; chi(2), P = 0.001) [1].
• Whereas colorectal cancers displayed a predominant pattern consisting of instability at the BAT loci (in 89% of tumors), TGF beta RII (73%), dinucleotide repeats (70%), MSH3 (43%), and BAX (30%), no such single pattern was discernible in endometrial cancers [12].
• There was also marginal evidence for a recessive protective effect with common homozygote as the baseline comparator for two SNPs-MSH6 rs3136245 (OR 0.67; 95% CI 0.46-0.98) and MSH3 rs6151662 (OR 0.28; 95% CI 0.08-0.91)-but the comparisons of genotype frequencies for these variants were not significant (P = 0.10 and 0.054) [13].

Anatomical context of MSH3

• Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4) [2].
• While MSH3 was frequently mutated in cell lines, BAX and TGFBR2 showed frequent alterations in both cell lines and xenografts [14].
• The endometrial tumor cell line HHUA carries mutations in two mismatch repair (MMR) genes MSH3 and MSH6 [15].
• Mismatch repair gene expression in malignant lymphoproliferative disorders of B-cell origin [16].
• Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium [17].

Associations of MSH3 with chemical compounds

• DHFR/MSH3 amplification in methotrexate-resistant cells alters the hMutSalpha/hMutSbeta ratio and reduces the efficiency of base-base mismatch repair [18].
• Because processing certain types of DNA damage by the mismatch repair pathway has also been implicated in tumor sensitivity to agents such as cisplatin, changes in expression at the DHFR/MSH3 locus may have further relevance to the outcome of multi-drug treatment regimens [19].
• After 5-aza-dC treatment, MSH3 expression was significantly enhanced in TCC and UMUC bladder cancer cells when compared to untreated cells [20].
• These studies support the idea that hMSH2-hMSH3 functions as an adenosine nucleotide-regulated molecular switch that must be activated by mismatched nucleotides for classical mismatch repair to occur [21].
• Mismatch repair (MMR) is initiated by MutS family proteins (MSH) that recognize DNA mismatches and recruit downstream repair factors [22].

Physical interactions of MSH3

• hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6 [23].

Enzymatic interactions of MSH3

• Sixty five percent of the patients deleted at hMLH1 were also deleted at hMSH3 [24].

Other interactions of MSH3

• In contrast, in cells that overexpress MSH3, the available MSH2 protein is sequestered predominantly into MutSbeta [25].
• Similar to MSH3 and MSH6, MLH3 harbors mononucleotide repeats, ie, (A(6))-(A(9)), in its coding region, which makes it a putative target for somatic mutations in MSI-positive tumors [26].
• Transfer of either chromosome 5 (hMSH3) or 2 (hMSH6) into HHUA cells partially corrects instability at the microsatellite loci and also the substitution and frameshift mutator phenotypes at the HPRT locus [27].
• Frameshift mutations in TGFbetaRII, BAX, MSH3 and MSH6 genes respectively were present in 4, 1, 2 and 2 of 34 ECOPC patients [28].
• Mismatch repair in extracts of Werner syndrome cell lines [29].

Analytical, diagnostic and therapeutic context of MSH3

• A subset of tumors were investigated for methylation of the 5' promoter region of MSH3 using Southern blot hybridization [30].
• Western blot analysis for the expression of MMR proteins demonstrated decreased hMSH6 and increased hMSH3 in RA synovium [31].
• Using PCR, we amplified regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6 from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+ gastric carcinomas, and 32 RER- gastric tumors [32].
• METHODS: Synovial tissues from patients with RA, osteoarthritis (OA), or normal subjects were analysed by immunohistochemistry using monoclonal antibodies to hMSH2, hMSH3, and hMSH6 [33].
• Mismatch repair expression is altered in a subset of prostate cancers (PCs) and a recent study suggested that time to biochemical recurrence following prostatectomy correlated with the degree of hMSH2 immunohistochemical staining [34].

References