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FLASH GENE

Symbol

MSH6

contributors: mct - updated : 15-09-2016

HGNC name	mutS homolog 6 (E. coli)
HGNC id	7329

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMMRD constitutional mismatch repair-deficiency syndrome HNPCC5 hereditary non polyposis colorectal cancer, type 5
Location	2p16.3      Physical location : 48.010.220 - 48.034.084
Synonym name	G/T mismatch binding protein
	sperm-associated protein
	DNA mismatch repair protein MSH6
	MutS-alpha 160 kDa subunit
Synonym symbol(s)	GTBP, HSAP, GTMBP, p160

DNA

TYPE	functioning gene
STRUCTURE	23.87 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site
text structure	GC rich site of translation initiation binding sites for Sp1, ETF, MTF1, AP1

MAPPING

cloned

Y

linked

N

status

confirmed

Map	pter - LHCGR - D2S119 - FOXN2 - D2S2182 - MSH2 - MSH6 - D2S378 - D2S391 - PIGF - FSHR - D2S2227 - D2S123 - SPTBN1 - D2S2251 - D2S393 - D2S337 - cen

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000179 10 - 4435 NP_000170 160 1360 - 1997 9455487 also called GTBP-N variant 2 - splicing - isoform 2 - - - 1997 9455487 also called GTB-I lacking a highly conserved region between GTB, MSH2, MSH3

EXPRESSION

Type

widely

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 blood / hematopoietic thymus         Cardiovascular heart         Reproductive male system testis     highly Respiratory respiratory tract trachea     highly Visual eye       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective adipose     highly Lymphoid

cell lineage

cell lines

fluid/secretion

at STAGE

cell cycle

cell cycle, G1

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal region (NTR), with a PCNA binding motif, a large region of unknown function and a nonspecific DNA binding fragment , which binds to duplex DNA in a salt-sensitive, mismatch-independent manner
	HATH domain (homologous to the N terminus of hepatoma derived growth factor HDGF)
	a core region structurally and functionally similar to bacterial MutS
	a PWWP domain, in the NTR, globular PWWP domain, binding double-stranded DNA, without any preference for mismatches or nicks, whereas its apparent affinity for single-stranded DNA is about 20 times lower

mono polymer

heteromer , dimer

HOMOLOGY

interspecies	homolog to E.coli muts S,6
	homolog to murine Msh6
	homolog to C.elegans Y47G6A.11

Homologene

FAMILY

DNA mismatch repair MUTS family

CATEGORY

DNA associated

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	restoring repair of base-base and single- nucleotide insertion-deletion mismatches
	role in suppressing genome instability and radiation-induced mutations
	in complex with MSH2, is the mismatch repair protein that mediates DNA repair through the recognition of 1- and 2-bp mismatches
	mismatch recognition heterodimer MSH2-hMSH6 disassembles a nucleosome
	is potentially involved in the somatic hypermutation (SHM) process
	is potentially involved in both the induction and repair of DNA double-strand breaks in switch regions
	mismatch repair protein MSH2-MSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

CELLULAR PROCESS

nucleotide, repair, mismatch repair

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

mismatch repair

a component	complexing with MSH2 in mismatch repair (MUTS alpha heterodimer), functioning as a molecular switch between ADP and ATP bound forms, selective for repair or GT mispair and single deplaced bases
	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

INTERACTION

DNA	binding to GT

RNA

small molecule

protein	MSH2 (heterodimer with MSH2 that is capable of recognizing a DNA mismatch)
	MSH3 to tumor supression
	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

ASSOCIATED DISORDERS

corresponding disease(s)

HNPCC5 , CMMRD

related resource

Hereditary Non-Polyposis Colorectal Cancer, HNPCC

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   deletion     in sporadic colorectal cancer (early onset), putatively in Mt DNA metabolism tumoral germinal mutation       in early-onset colorectal cancer patients without family history and endometrial carcinoma tumoral     --low   in cervical cancer tumoral       loss of function in colon and uterus tumor tumoral germinal mutation       associated with Lynch syndrome cancers (accountng for 10-20p100 of Lynch syndrome colorectal cancers) tumoral germinal mutation     loss of function in patients with primary ovarian, fallopian tube, or peritoneal cancers

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