MSH3 mutS homolog 3 (E. coli)

2006-07-01 Enric Domingo , Simo Schwartz Jr Affiliation

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 ID	Last Year	Title	Authors
11980631	2002	Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability.	Duval A et al
2722860	1989	Isolation 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
7669036	1995	Loss of expression of the human MSH3 gene in hematological malignancies.	Inokuchi K et al
11900875	2002	DNA mismatch repair defects: role in colorectal carcinogenesis.	Jacob S et al
8782829	1996	Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair.	Risinger JI et al
8838312	1996	Genomic organization and expression of the human MSH3 gene.	Watanabe A et al
10545954	1999	HNPCC-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 ID	Transcript ID	Uniprot
ENSG00000113318	ENST00000265081	P20585
ENSG00000113318	ENST00000658259	A0A590UJW0
ENSG00000113318	ENST00000659302	A0A590UK39
ENSG00000113318	ENST00000667069	A0A590UJN8
ENSG00000113318	ENST00000670357	A0A590UKC9

Expression (GTEx)

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

Pathway	Source	External ID
Mismatch repair	KEGG	ko03430
Colorectal cancer	KEGG	ko05210
Mismatch repair	KEGG	hsa03430
Pathways in cancer	KEGG	hsa05200
Colorectal cancer	KEGG	hsa05210
DNA Repair	REACTOME	R-HSA-73894
Mismatch Repair	REACTOME	R-HSA-5358508
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	REACTOME	R-HSA-5358606
Platinum drug resistance	KEGG	ko01524
Platinum drug resistance	KEGG	hsa01524

PharmGKB

Entity ID	Name	Type	Evidence	Association	PD	PMIDs
PA128406956	fluorouracil	Chemical	VariantAnnotation	not associated	PD	28796378
PA164713176	Platinum compounds	Chemical	VariantAnnotation	not associated	PD	28796378
PA166122986	radiotherapy	Chemical	VariantAnnotation	not associated	PD	28796378
PA445742	Stomach Neoplasms	Disease	VariantAnnotation	not associated	PD	28796378

References

Pubmed ID	Year	Title	Citations
38281411	2024	High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.	0
38281411	2024	High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.	0
35675019	2023	A large family with MSH3-related polyposis.	3
37140056	2023	MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.	5
37402566	2023	MSH3: a confirmed predisposing gene for adenomatous polyposis.	2
37888748	2023	Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate‑resistant human colorectal cancer cells.	0
35675019	2023	A large family with MSH3-related polyposis.	3
37140056	2023	MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.	5
37402566	2023	MSH3: a confirmed predisposing gene for adenomatous polyposis.	2
37888748	2023	Novel insights into the ecDNA formation mechanism involving MSH3 in methotrexate‑resistant human colorectal cancer cells.	0
33596761	2021	Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.	13
34250384	2021	Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population.	7
33596761	2021	Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.	13
34250384	2021	Prevalence and Characterization of Biallelic and Monoallelic NTHL1 and MSH3 Variant Carriers From a Pan-Cancer Patient Population.	7
31549400	2020	EMAST 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/msh3id341ch5q11