MSH3 mutS homolog 3 (E. coli)

2006-07-01   Enric Domingo  , Simo Schwartz Jr  

Oncologia Molecular i Envelliment, Centre dInvestigacions en Bioqumica i Biologia Molecular (CIBBIM) Hospital Universitari Vall dHebron Passeig Vall dHebron 119-129 Barcelona 08035, Catalonia, Spain

Identity

HGNC
MSH3
LOCATION
5q14.1
LOCUSID
4437
ALIAS
DUP,FAP4,MRP1
FUSION GENES
Show Gene Fusions

DNA/RNA

Description

The MSH3 gene is composed of 24 exons spanning in a region of 222 Kb.

Transcription

There are two major transcripts of 5 kb and 3,8 kb under the control of two different polyadenilation sites.

Proteins

Description

Amino acids: 1137. Molecular Weight: 127 KDa. MSH3 is a protein involved in the mismatch repair process after DNA replication.

Expression

Expression of MSH3 together with the dihydrofolate reductase (DHFR) gene appear to be regulated by a bidirectional promoter composed of multiple GC boxes and two initiator elements. MSH3 is expressed in all human tissues at low levels but with variable intensities, with higher expression in testis and pancreas and lower in small intestine and colon.

Function

MSH3 binds to MSH2 to form the MutSb heterodimer, which binds to insertion-deletion mismatches of two or more base pairs. Thereafter the MutS complex associates with the MutL complex and recruits the proteins needed for DNA excision and repair.

Homology

MSH3 is homologue to the bacterial MutS gene and to the Msh3 gene in S. cerevisiae. Homology is higher in the C-terminal region.

Mutations

Somatic

MSH3 has insertions/deletions in a A(8) repeat in tumours showing microsatellite instability (MSI). As MSH3 is a mismatch repair gene and is mutated in a microsatellite only in MSI tumours is considered to be a secondary mutator that enhances a more severe MSI.

Implicated in

Entity name
MSI (MicroSatellite Instability).
Note
Tumours in which the molecular feature that leads to cancer is the lost of the mismatch repair (MMR) system.
Disease
This phenotype is present in 15% of colorectal cancer, gastric cancer and endometrial cancer, and with lower incidence in some other tissues.
Oncogenesis
The average frequencies of the microsatellite mutation reported in sporadic MSI from colorectal, gastric and endometrial cancer are 38%, 39% and 25% respectively. In hereditary MSI (or HNPCC) is 51%.
Entity name
Hematological malignancies.
Oncogenesis
It has been reported loss of expression of MSH3 at the mRNA level in some hematological malignancies including chronic myelogenous leukemia and acute myelogenous leukemia, acute lymphocytic leukemia and myelodysplastic syndrome.

Article Bibliography

Pubmed IDLast YearTitleAuthors
119806312002Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability.Duval A et al
27228601989Isolation and characterization of cDNA clones derived from the divergently transcribed gene in the region upstream from the human dihydrofolate reductase gene.Fujii H et al
76690361995Loss of expression of the human MSH3 gene in hematological malignancies.Inokuchi K et al
119008752002DNA mismatch repair defects: role in colorectal carcinogenesis.Jacob S et al
87828291996Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.Risinger JI et al
88383121996Genomic organization and expression of the human MSH3 gene.Watanabe A et al
105459541999HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions.de Wind N et al

Other Information

Locus ID:

NCBI: 4437
MIM: 600887
HGNC: 7326
Ensembl: ENSG00000113318

Variants:

dbSNP: 4437
ClinVar: 4437
TCGA: ENSG00000113318
COSMIC: MSH3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000113318ENST00000265081P20585
ENSG00000113318ENST00000658259A0A590UJW0
ENSG00000113318ENST00000659302A0A590UK39
ENSG00000113318ENST00000667069A0A590UJN8
ENSG00000113318ENST00000670357A0A590UKC9

Expression (GTEx)

0
5
10
15
Adipose - Subcutaneous
Adipose - Visceral
Adrenal Gland
Artery - Aorta
Artery - Tibial
Bladder
Brain - Amygdala
Brain - Anterior cingulate cortex
Brain - Caudate
Brain - Cerebellar Hemisphere
Brain - Cerebellum
Brain - Cortex
Brain - Frontal Cortex
Brain - Hippocampus
Brain - Hypothalamus
Brain - Nucleus accumbens
Brain - Putamen
Brain - Spinal cord
Brain - Substantia nigra
Breast - Mammary Tissue
Cells - Cultured fibroblasts
Cells - EBV - transformed lymphocytes
Cervix - Ectocervix
Cervix - Endocervix
Colon - Sigmoid
Colon - Transverse
Esophagus - Gastroesophageal Junction
Esophagus - Mucosa
Esophagus - Muscularis
Fallopian Tube
Heart - Atrial Appendage
Heart - Left Ventricle
Kidney - Cortex
Kidney - Medulla
Liver
Lung
Minor Salivary Gland
Muscle - Skeletal
Nerve - Tibial
Ovary
Pancreas
Pituitary
Prostate
Skin - Not Sun Exposed
Skin - Sun Exposed
Small Intestine - Terminal Ileum
Spleen
Stomach
Testis
Thyroid
Uterus
Vagina
Whole Blood

Pathways

PathwaySourceExternal ID
Mismatch repairKEGGko03430
Colorectal cancerKEGGko05210
Mismatch repairKEGGhsa03430
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
DNA RepairREACTOMER-HSA-73894
Mismatch RepairREACTOMER-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)REACTOMER-HSA-5358606
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalVariantAnnotationnot associatedPD28796378
PA164713176Platinum compoundsChemicalVariantAnnotationnot associatedPD28796378
PA166122986radiotherapyChemicalVariantAnnotationnot associatedPD28796378
PA445742Stomach NeoplasmsDiseaseVariantAnnotationnot associatedPD28796378

References

Pubmed IDYearTitleCitations
382814112024High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.0
382814112024High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.0
356750192023A large family with MSH3-related polyposis.3
371400562023MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.5
374025662023MSH3: a confirmed predisposing gene for adenomatous polyposis.2
378887482023Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate‑resistant human colorectal cancer cells.0
356750192023A large family with MSH3-related polyposis.3
371400562023MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.5
374025662023MSH3: a confirmed predisposing gene for adenomatous polyposis.2
378887482023Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate‑resistant human colorectal cancer cells.0
335967612021Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.13
342503842021Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population.7
335967612021Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.13
342503842021Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population.7
315494002020EMAST status as a beneficial predictor of fluorouracil-based adjuvant chemotherapy for Stage II/III colorectal cancer.3

Citation

Enric Domingo ; Simo Schwartz Jr

MSH3 mutS homolog 3 (E. coli)

Atlas Genet Cytogenet Oncol Haematol. 2006-07-01

Online version: http://atlasgeneticsoncology.org/gene/341/gene-fusions/deep-insight-explorer/teaching-explorer/