MSH6

MSH6
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2O8F, 2GFU, 2O8B, 2O8C, 2O8D, 2O8E
Identifikatori
Aliasi	MSH6
Vanjski ID-jevi	OMIM: 600678 MGI: 1343961 HomoloGene: 149 GeneCards: MSH6
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	47,810,063 bp
Lokacija gena (miš)
Hrom.	Hromosom 17 (miš)
Kraj	88,298,320 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• nucleotide binding; • vezivanje sa DNK; • protein homodimerization activity; • mismatched DNA binding; • ADP binding; • chromatin binding; • oxidized purine DNA binding; • methylated histone binding; • oštećeno vezivanje sa DNK; • ATPase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • single thymine insertion binding; • four-way junction DNA binding; • MutLalpha complex binding; • double-stranded DNA binding; • ATP binding; • magnesium ion binding; • single guanine insertion binding; • guanine/thymine mispair binding; • ATP-dependent activity, acting on DNA; • vezivanje enzima;
Ćelijska komponenta	• Golđijev aparat; • intracellular membrane-bounded organelle; • MutSalpha complex; • nukleoplazma; • hromosom; • jedro; • citosol; • mismatch repair complex;
Biološki proces	• determination of adult lifespan; • cellular response to DNA damage stimulus; • positive regulation of isotype switching; • intrinsic apoptotic signaling pathway; • maintenance of DNA repeat elements; • positive regulation of helicase activity; • somatic recombination of immunoglobulin gene segments; • negative regulation of DNA recombination; • Popravak neusklađenosti DNK; • GO:0022415 viral process; • GO:0100026 Popravka DNK; • meiotic mismatch repair; • intrinsic apoptotic signaling pathway in response to DNA damage; • response to UV; • somatic hypermutation of immunoglobulin genes; • Promjena imunoglobulinske klase; • pyrimidine dimer repair; • mitotic G2 DNA damage checkpoint signaling; • negative regulation of DNA endoreduplication; • interstrand cross-link repair; • replication fork arrest;
	Izvori:Amigo / QuickGO
Ortolozi
	2956
	17688
	ENSG00000116062
	ENSMUSG00000005370
	P52701
	P54276
	NM_000179; NM_001281492; NM_001281493; NM_001281494
	NM_010830
	NP_000170; NP_001268421; NP_001268422; NP_001268423
	NP_034960
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

MSH6 ili mutS homolog 6 jest gen koji se kod ljudi nalazi na hromosomu 2. To je gen koji kodira protein Msh6 za popravak neusklađenosti DNK u pupajućem kvascu Saccharomyces cerevisiae. To je homolog ljudskog "G/T vezujućeg proteina" (GTBP) koji se također naziva p160 ili hMSH6 (ljudski MSH6). Protein MSH6 je član mutatora S (MutS), porodice proteina koji su uključeni u popravku oštećenja DNK.

Defekti u hMSH6 su povezani sa atipskim nasljednim nepolipoznim kolorektumskim karcinomom koji ne ispunjava Amsterdamske kriterije za HNPCC. Mutacije hMSH6 su takođe povezane sa karcinomom endometrija i razvojem karcinoma endometrijuma.

Otkriće

MSH6 je prvi put identificiran u kvascu S. cerevisiae zbog svoje homologije sa MSH2. Identifikacija ljudsog gena GTBP i naknadna dostupnost aminokiselinske sekvence pokazala je da su MSH6 kvasca i ljudski GTBP više povezani jedni s drugima nego bilo koji drugi MutS homolog, sa 26,6% aminokiselinskog identiteta.^[5] Tako je GTBP dobio ime ljudski MSH6 ili hMSH6.

Amiokiselininska sekvenca

Dužina polipeptidnog lanca je 1.360 aminokiselina, a molkekulska iežina 152.786 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MSRQSTLYSF	FPKSPALSDA	NKASARASRE	GGRAAAAPGA	SPSPGGDAAW
SEAGPGPRPL	ARSASPPKAK	NLNGGLRRSV	APAAPTSCDF	SPGDLVWAKM
EGYPWWPCLV	YNHPFDGTFI	REKGKSVRVH	VQFFDDSPTR	GWVSKRLLKP
YTGSKSKEAQ	KGGHFYSAKP	EILRAMQRAD	EALNKDKIKR	LELAVCDEPS
EPEEEEEMEV	GTTYVTDKSE	EDNEIESEEE	VQPKTQGSRR	SSRQIKKRRV
ISDSESDIGG	SDVEFKPDTK	EEGSSDEISS	GVGDSESEGL	NSPVKVARKR
KRMVTGNGSL	KRKSSRKETP	SATKQATSIS	SETKNTLRAF	SAPQNSESQA
HVSGGGDDSS	RPTVWYHETL	EWLKEEKRRD	EHRRRPDHPD	FDASTLYVPE
DFLNSCTPGM	RKWWQIKSQN	FDLVICYKVG	KFYELYHMDA	LIGVSELGLV
FMKGNWAHSG	FPEIAFGRYS	DSLVQKGYKV	ARVEQTETPE	MMEARCRKMA
HISKYDRVVR	REICRIITKG	TQTYSVLEGD	PSENYSKYLL	SLKEKEEDSS
GHTRAYGVCF	VDTSLGKFFI	GQFSDDRHCS	RFRTLVAHYP	PVQVLFEKGN
LSKETKTILK	SSLSCSLQEG	LIPGSQFWDA	SKTLRTLLEE	EYFREKLSDG
IGVMLPQVLK	GMTSESDSIG	LTPGEKSELA	LSALGGCVFY	LKKCLIDQEL
LSMANFEEYI	PLDSDTVSTT	RSGAIFTKAY	QRMVLDAVTL	NNLEIFLNGT
NGSTEGTLLE	RVDTCHTPFG	KRLLKQWLCA	PLCNHYAIND	RLDAIEDLMV
VPDKISEVVE	LLKKLPDLER	LLSKIHNVGS	PLKSQNHPDS	RAIMYEETTY
SKKKIIDFLS	ALEGFKVMCK	IIGIMEEVAD	GFKSKILKQV	ISLQTKNPEG
RFPDLTVELN	RWDTAFDHEK	ARKTGLITPK	AGFDSDYDQA	LADIRENEQS
LLEYLEKQRN	RIGCRTIVYW	GIGRNRYQLE	IPENFTTRNL	PEEYELKSTK
KGCKRYWTKT	IEKKLANLIN	AEERRDVSLK	DCMRRLFYNF	DKNYKDWQSA
VECIAVLDVL	LCLANYSRGG	DGPMCRPVIL	LPEDTPPFLE	LKGSRHPCIT
KTFFGDDFIP	NDILIGCEEE	EQENGKAYCV	LVTGPNMGGK	STLMRQAGLL
AVMAQMGCYV	PAEVCRLTPI	DRVFTRLGAS	DRIMSGESTF	FVELSETASI
LMHATAHSLV	LVDELGRGTA	TFDGTAIANA	VVKELAETIK	CRTLFSTHYH
SLVEDYSQNV	AVRLGHMACM	VENECEDPSQ	ETITFLYKFI	KGACPKSYGF
NAARLANLPE	EVIQKGHRKA	REFEKMNQSL	RLFREVCLAS	ERSTVDAEAV
HKLLTLIKEL

Struktura

U ljudskom genomu, hMSH6 nalazi se na hromozomu 2. Sadrži strukturni motiv koji vezuje Walker-A/B adeninski nukleotid, što je najkonzerviranija sekvenca pronađena u svim MutS homolozima.^[7] Kao i kod drugih MutS homologa, hMSH6 ima unutrašnju aktivnost ATPaze. Funkcionira isključivo kada je vezan za hMSH2 kao heterodimer, iako sam hMSH2 može funkcionirati kao homomultimer ili kao heterodimer s hMSH3.^[8]

Funkcija

Značaj popravke neusklađenosti

Nepodudarnosti se obično javljaju kao rezultat grešaka u replikaciji DNK, genetičke rekombinacije ili drugih hemijskih i fizičkih faktora.^[9] Prepoznavanje tih neusklađenosti i njihovo popravljanje izuzetno je važno za ćelije, jer neuspjeh u tome rezultira nestabilnošću mikrosatelita, povećanom stopom spontanih mutacija (fenotip mutatora) i osjetljivošću na HNPCC..^[7]^[10] hMSH6 se kombinuje sa hMSH2 i formira aktivni proteinski kompleks, hMutS alfa, koji se također naziva i hMSH2-hMSH6.

Prepoznavanje neusklađenosti

Prepoznavanje neusklađenosti putem ovog kompleksa regulirano je transformacijom ADP → ATP, što pruža dokaz da hMutS alfa kompleks funkcionira kao molekulni prekidač.^[11] U normalnoj DNK, adenin (A) se vezuje za timin (T), a citozin (C) se vezuje za guanin (G). Ponekad će doći do neusklađenosti u kojoj će se T povezati sa G, što se naziva G/T neusklađenost. Kada se prepozna G/T neusklađenost, hMutS alfa kompleks se veže i razmjenjuje ADP za ATP.^[10] Razmjena ADP → ATP uzrokuje konformacijsku promjenu za pretvaranje hMutS alfa u kliznu stezaljku koja može difundirati duž DNK kičme.^[10] ATP inducira oslobađanje kompleksa iz DNK i omogućava hMutS alfa da se disocira duž DNK kao klizna stezaljka. Ova transformacija pomaže u pokretanju nizvodnih događaja za popravku oštećene DNK.^[10]

Kancer

Iako mutacije u hMSH2 uzrokuju jak opći fenotip mutatora, mutacije u hMSH6 uzrokuju samo skroman muttorski fenotip.^[5] Na nivou gena, otkriveno je da mutacije uzrokuju prvenstveno mutacije supstitucije na jednoj bazi, što sugerira da uloga hMSH6 prvenstveno je za ispravljanje mutacija supstitucije jedne baze i u manjoj mjeri mutacija insercije/delecije jedne baze.^[5]

Mutacije u genu hMSH6 uzrokuju da protein bude nefunkcionalan ili samo djelomično aktivan, čime se smanjuje njegova sposobnost popravljanja grešaka u DNK. Gubitak funkcije MSH6 rezultira nestabilnošću kod ponavljanja mononukleotida.^[5] HNPCC je najčešće uzrokovan mutacijama u hMSH2 i hMLH1, ali mutacije u hMSH6 povezane su s atipskim oblikom HNPCC.^[12] Čini se da je penetrantnost kolorektumskog karcinoma niža u ovim mutacijama, što znači da je nizak udio nositelja mutacije hMSH6 prisutan sa bolešću. Rak endometrija, s druge strane, čini se važnijom kliničkom manifestacijom za žene nositeljice mutacije. Početak raka endometrija, kao i raka debelog crijeva u porodicama sa hMSH6 mutacijama je oko 50 godina. Ovo je odgođeno u poređenju sa pojavom tumora povezanih s hMSH2 u dobi od 44 godine.^[12]

Epigenetička kontrola MSH6 kod kancera

Dvije mikroRNK, miR21 i miR-155, ciljaju gene hMSH6 i hMSH2 za popravak DNK neusklađenosti (MMR), da uzrokuju smanjenu ekspresiju njihovih proteina.^[13]^[14] Ako je jedna ili druga od ove dvije mikroRNK pretjerano eksprimirana, proteini hMSH2 i hMSH6 su nedovoljno eksprimirani, što rezultira smanjenom popravkom neusklađenosti DNK i povećanom nestabilnošću mikrosatelita.

Jedna od ovih mikroRNK, miR21, regulirana je epigenetički metilacijskoh stanja CpG-ostrva u jednj ili drugoj od svoje dvije promotorske regije.^[15] Hipometilacija njegovog promotorskog regionapovezana je se povećanom ekspresijom miRNK.^[16] Visoka ekspresija mikroRNK izaziva represiju tih ciljnih gena (vidi mikroRNK utišavanje gena). U 66% do 90% oslučajeva raka debelog crijeva, miR-21 je nadeksprimiran,^[13] a općenito mjereni nivoi hMSH2 opadaju (a hMSH6 je nestabilan bez hMSH2^[14]).

Kada je miR-155 bio povišen, hMSH2 je bio nedovoljno eksprimiran u 44% do 67% istih tkiva (a hMSH6 je vjerovatno i nedovoljno eksprimiran, a također je nestabilan u odsustvu hMSH2).^[14]

Interakcije

Pokazano je da MSH6 reagruje sa MSH2,^[17]^[18]^[19]^[20]^[21] PCNA^[22]^[23]^[24] i BRCA1.^[17]^[25]

Također pogledajte

Reparacija DNK

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000116062 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000005370 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c ^d Marsischky GT, et al. (1996). "Redundancy of Saccharomyces cerevisiae MSH3 and MSH6 in MSH2-dependent mismatch repair". Genes Dev. 10 (4): 407–20. doi:10.1101/gad.10.4.407. PMID 8600025.
^ "UniProt, P52701" (jezik: engleski). Pristupljeno 13. 11. 2021.
^ ^a ^b Fishel R, Kolodner RD (1995). "Identification of mismatch repair genes and their role in the development of cancer". Current Opinion in Genetics & Development. 5 (3): 382–95. doi:10.1016/0959-437X(95)80055-7. PMID 7549435.
^ Acharya S, et al. (1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". PNAS. 93 (24): 13629–34. Bibcode:1996PNAS...9313629A. doi:10.1073/pnas.93.24.13629. PMC 19374. PMID 8942985.
^ Friedberg EC, Walker GC, Siede W. (1995). DNA repair and mutagenesis. American Society for Microbiology, Washington DC.
^ ^a ^b ^c ^d Gradia S, et al. (1999). "hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA". Molecular Cell. 3 (2): 255–61. doi:10.1016/S1097-2765(00)80316-0. PMID 10078208.
^ Gradia S, Acharya S, Fishel R (1997). "The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch". Cell. 91 (7): 995–1005. doi:10.1016/S0092-8674(00)80490-0. PMID 9428522. S2CID 3551402.
^ ^a ^b Wagner A, et al. (2001). "Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree". J. Med. Genet. 38 (5): 318–22. doi:10.1136/jmg.38.5.318. PMC 1734864. PMID 11333868.
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^ Baer C, Claus R, Plass C (2013). "Genome-wide epigenetic regulation of miRNAs in cancer". Cancer Res. 73 (2): 473–7. doi:10.1158/0008-5472.CAN-12-3731. PMID 23316035.
^ Aure MR, Leivonen SK, Fleischer T, Zhu Q, Overgaard J, Alsner J, Tramm T, Louhimo R, Alnæs GI, Perälä M, Busato F, Touleimat N, Tost J, Børresen-Dale AL, Hautaniemi S, Troyanskaya OG, Lingjærde OC, Sahlberg KK, Kristensen VN (2013). "Individual and combined effects of DNA methylation and copy number alterations on miRNA expression in breast tumors". Genome Biol. 14 (11): R126. doi:10.1186/gb-2013-14-11-r126. PMC 4053776. PMID 24257477.
^ ^a ^b Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (Apr 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes & Development. 14 (8): 927–39. doi:10.1101/gad.14.8.927 (neaktivno 31. 10. 2021). PMC 316544. PMID 10783165.CS1 održavanje: DOI nije aktivan od 2021 (link)
^ Wang Y, Qin J (Dec 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proceedings of the National Academy of Sciences of the United States of America. 100 (26): 15387–92. Bibcode:2003PNAS..10015387W. doi:10.1073/pnas.2536810100. PMC 307577. PMID 14657349.
^ Guerrette S, Wilson T, Gradia S, Fishel R (Nov 1998). "Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer". Molecular and Cellular Biology. 18 (11): 6616–23. doi:10.1128/mcb.18.11.6616. PMC 109246. PMID 9774676.
^ Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R (Feb 1999). "hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis". Cancer Research. 59 (4): 816–22. PMID 10029069.
^ Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (Nov 1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". Proceedings of the National Academy of Sciences of the United States of America. 93 (24): 13629–34. Bibcode:1996PNAS...9313629A. doi:10.1073/pnas.93.24.13629. PMC 19374. PMID 8942985.
^ Kleczkowska HE, Marra G, Lettieri T, Jiricny J (Mar 2001). "hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci". Genes & Development. 15 (6): 724–36. doi:10.1101/gad.191201. PMC 312660. PMID 11274057.
^ Clark AB, Valle F, Drotschmann K, Gary RK, Kunkel TA (Nov 2000). "Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes". The Journal of Biological Chemistry. 275 (47): 36498–501. doi:10.1074/jbc.C000513200. PMID 11005803.
^ Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T (Oct 2002). "A proteomics approach to identify proliferating cell nuclear antigen (PCNA)-binding proteins in human cell lysates. Identification of the human CHL12/RFCs2-5 complex as a novel PCNA-binding protein". The Journal of Biological Chemistry. 277 (43): 40362–7. doi:10.1074/jbc.M206194200. PMID 12171929.
^ Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI (Aug 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene. 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787.

Dopunska literatura

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Vanjski linkovi

FAQs on HNPCC Arhivirano 15. 8. 2007. na Wayback Machine from the National Institute of Health
GeneReviews/NCBI/NIH/UW entry on Lynch syndrome
MSH6 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000116062 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000005370 - Ensembl, maj 2017

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