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FLASH GENE

Symbol

MSH2

contributors: np/shn/mct - updated : 15-09-2016

HGNC name	mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli)
HGNC id	7325

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMMRD constitutional mismatch repair-deficiency syndrome HNPCC1 hereditary nonpolyposis colorectal cancer, type 1 MTS Muir-Torre syndrome
Location	2p21      Physical location : 47.630.262 - 47.710.360
Synonym name	mutS (E. coli) homolog 2 (colon cancer, nonpolyposis type 1)
	MutS protein homolog 2
Synonym symbol(s)	FCC1, COCA1, HNPCC, LCFS2, HNPCC1

DNA

TYPE	functioning gene
STRUCTURE	80.16 kb     16 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - D2S288 - D2S2227 - MSH2 - D2S2739 - D2S1352 - cen

RNA

TRANSCRIPTS	type	messenger

text	several spliced transcripts lacking one or other exons,expressed in monocytes and normal colon mucosa (PMID: 10573010)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000251 16 splicing 3145 NP_000242 - 934 - 2005 15886699 NM_001258281 16 splicing 3042 NP_001245210 - 868 - 2005 15886699

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine small intestine       Lymphoid/Immune lymph node           thymus       highly   tonsils       highly Reproductive male system testis     highly Skin/Tegument skin

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal connector and lever domains (Domain 3 and 2) involved in protein stability (Ollila 2008)
	a region of homology with other MutS or MutL homologs, with 150 aminoacids
	a putative helix-turn-helix domain associated with an adenine nucleotide
	magnesium binding site
	the clamp domain (Domain 4)
	an ATPase domain (Domain 5) involved in mismatch binding or release (Ollila 2008)
	C-terminus containing a helix-turn-helix-motif, which stabilize the ATPase domains of the MutSa subunits

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	ortholog to MSH2, Pan troglodytes
	ortholog to msh2, Danio rerio
	ortholog to Msh2, Rattus norvegicus
	ortholog to Msh2, Mus musculus

Homologene

FAMILY

DNA mismatch repair mutS family

CATEGORY

DNA associated

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	regulates adenosine nucleotide processing by the MSH2-MSH6 mismatch recognition heterodimer
	MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions
	MSH2-MSH3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions
	MSH2-MSH3 is required for 3prime non-homologous tail removal in double-strand break repair and, MSH2-MSH3 binds double-strand/single-strand junctions and initiates repair in an ATP-dependent manner
	MSH2-MSH3 suppresses chromosomal instability and modulates the tumor spectrum in TP53-deficient tumorigenesis and possibly has a role in other chromosomally unstable tumors as well
	mismatch repair protein MSH2-MSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate
	MSH2-MSH3 plays an important role in shifting the expansion-contraction equilibrium toward expansion in the early stages of Trinucleotide repeat (TNR) tract expansion
	having function in correcting nucleotide mismatches or insertions and deletions in duplex DNA caused by errors in DNA replication or recombination

CELLULAR PROCESS

nucleotide, repair, mismatch repair

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

mismatch repair

a component	complexing with GTBP (MUTS alpha heterodimer)
	associated primarily with MSH6 in a heterodimer called MutSa
	part of MSH2-MSH6-MLH1-PMS1 ternary complexes requiring ATP binding to only the MSH6 nucleotide-binding site, whereas the formation of MSH2-MSH6 sliding clamps requires ATP binding to both the MSH2 and MSH6 nucleotide-binding sites
	MSH2-MSH3 heterodimer recognizes various DNA mispairs, including loops of DNA ranging from 1 to 14 nucleotides and some base-base mispairs

INTERACTION

DNA	mismatched nucleotides

RNA

small molecule	nucleotide, other,
	ADP and magnesium

protein	MSH3 and MSH6
	exonuclease I, EXO1
	MSH6, MLH1, and PMS2
	BRCA1
	5'-3' exonuclease 1, EXO1/HEX1
	p53
	checkpoint kinase 2, CHK2
	c-MYC and MAX
	ATM- and Rad3-related, ATR
	excision repair cross-complementing rodent repair deficiency, complementation group 1 (includes overlapping antisense sequence), ERCC1
	MSH2/6 formed a complex with BLM-p53-RAD51 in response to the damaged DNA forks during double-stranded break repair
	Chk1 and Chk2
	PKC zeta
	Oestrogen receptor alpha/beta
	Werner syndrome, RecQ helicase-like, WRN
	FANCD2
	MLH1-MLH3, a meiotic crossover and DNA mismatch repair factor, is a MSH2-MSH3-stimulated endonuclease
	MSH2 interacts with MSH6 or MSH3 to form the MutSalpha or MutSbeta complex, respectively, which recognize base-base mispairs and insertions/deletions and initiate the repair process

cell & other

REGULATION

repressed by

Bcl-2

ASSOCIATED DISORDERS

corresponding disease(s)

HNPCC1 , MTS , CMMRD

related resource

InternationalGrouponHereditaryNon-PolyposisColorectalCancer

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function in colon and uterus tumor tumoral germinal mutation       germline allele-specific and mosaic hypermethylation, without evidence of DNA mismatch repair gene mutation in early-onset colorectal or endometrial cancers tumoral germinal mutation       in epithelial ovarian cancer

Susceptibility

to prostate cancer

Variant & Polymorphism other	rare genetic variants that confer a high risk of prostate cancer when mutated

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	MSH2-/- mice are viable but develop lymphoid tumours
	mouse Msh2-deficient cells have lost mismatch binding and have acquired microsatellite instability, a mutator phenotype, and tolerance to methylating agents. A significant fraction of Msh2-deficient mice develop lymphomas at an early age
	MSH2-/- mice develop lymphoblastic lymphomas in association with aberrant expression of rhombotin-2 and Tal-1
	ES cells from Msh2(+/-) and Msh2(-/-) mice accumulate oxidized bases as a consequence of low-level radiation exposure
	absence of Msh2 in Hdh(Q111) mice is sufficient to abrogate progressive Huntington's disease CAG repeat expansion in striatum, eliminate striatal mutant huntingtin with somatically expanded glutamine tracts and to cause an approximately 5 month delay in nuclear mutant protein accumulation
	MSH2 depletion caused cellular phenotypes associated with defective Fanconi Anemia pathway, including mitomycin C hypersensitivity and chromosomal instability
	Msh2-null mice were also impaired in locomotive activity and had an abnormal response to heat