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MSH2

S Wikipedije, slobodne enciklopedije
MSH2
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

2O8B, 2O8C, 2O8D, 2O8E, 2O8F, 3THW, 3THX, 3THY, 3THZ

Identifikatori
AliasiMSH2
Vanjski ID-jeviOMIM: 609309 MGI: 101816 HomoloGene: 210 GeneCards: MSH2
Lokacija gena (čovjek)
Hromosom 2 (čovjek)
Hrom.Hromosom 2 (čovjek)[1]
Hromosom 2 (čovjek)
Genomska lokacija za MSH2
Genomska lokacija za MSH2
Bend2p21-p16.3Početak47,403,067 bp[1]
Kraj47,663,146 bp[1]
Lokacija gena (miš)
Hromosom 17 (miš)
Hrom.Hromosom 17 (miš)[2]
Hromosom 17 (miš)
Genomska lokacija za MSH2
Genomska lokacija za MSH2
Bend17 E4|17 57.87 cMPočetak87,979,758 bp[2]
Kraj88,031,141 bp[2]
Obrazac RNK ekspresije
Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija vezivanje sa DNK
nucleotide binding
protein homodimerization activity
mismatched DNA binding
dinucleotide insertion or deletion binding
ADP binding
centromeric DNA binding
oxidized purine DNA binding
single-stranded DNA binding
oštećeno vezivanje sa DNK
ATPase activity
protein C-terminus binding
GO:0001948, GO:0016582 vezivanje za proteine
single thymine insertion binding
four-way junction DNA binding
MutLalpha complex binding
vezivanje enzima
double-stranded DNA binding
dinucleotide repeat insertion binding
ATP binding
protein kinase binding
magnesium ion binding
single guanine insertion binding
guanine/thymine mispair binding
Y-form DNA binding
heteroduplex DNA loop binding
double-strand/single-strand DNA junction binding
ATP-dependent activity, acting on DNA
chromatin binding
Ćelijska komponenta MutSbeta complex
membrana
MutSalpha complex
nukleoplazma
mismatch repair complex
jedro
hromosom
Biološki proces GO:1904089 negative regulation of neuron apoptotic process
germ cell development
male gonad development
Postreplikacijska reparacija
determination of adult lifespan
in utero embryonic development
cellular response to DNA damage stimulus
Oksidacijska fosforilacija
maintenance of DNA repeat elements
positive regulation of helicase activity
somatic recombination of immunoglobulin gene segments
intrinsic apoptotic signaling pathway in response to DNA damage
negative regulation of DNA recombination
somatic recombination of immunoglobulin genes involved in immune response
Popravak neusklađenosti DNK
B cell differentiation
B cell mediated immunity
GO:0100026 Popravka DNK
positive regulation of isotype switching to IgA isotypes
positive regulation of isotype switching to IgG isotypes
double-strand break repair
meiotic gene conversion
response to X-ray
response to UV-B
somatic hypermutation of immunoglobulin genes
mitotic intra-S DNA damage checkpoint signaling
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
negative regulation of reciprocal meiotic recombination
Promjena imunoglobulinske klase
protein localization to chromatin
DNA recombination
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)

NM_000251
NM_001258281

NM_008628

RefSeq (bjelančevina)

NP_000242
NP_001245210

NP_032654

Lokacija (UCSC)Chr 2: 47.4 – 47.66 MbChr 17: 87.98 – 88.03 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Protein Msh2 popravka neusklađenosti DNK , poznat i kao MutS homolog 2 ili MSH2 jest protein koji je kod ljudi kodiran genom MSH2 sa hromosoma 2.

Amiokiselininska sekvenca

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Dužina polipeptidnog lanca je 934 aminokiseline, a molkekulska iežina 104.743 Da.[5]

1020304050
MAVQPKETLQLESAAEVGFVRFFQGMPEKPTTTVRLFDRGDFYTAHGEDA
LLAAREVFKTQGVIKYMGPAGAKNLQSVVLSKMNFESFVKDLLLVRQYRV
EVYKNRAGNKASKENDWYLAYKASPGNLSQFEDILFGNNDMSASIGVVGV
KMSAVDGQRQVGVGYVDSIQRKLGLCEFPDNDQFSNLEALLIQIGPKECV
LPGGETAGDMGKLRQIIQRGGILITERKKADFSTKDIYQDLNRLLKGKKG
EQMNSAVLPEMENQVAVSSLSAVIKFLELLSDDSNFGQFELTTFDFSQYM
KLDIAAVRALNLFQGSVEDTTGSQSLAALLNKCKTPQGQRLVNQWIKQPL
MDKNRIEERLNLVEAFVEDAELRQTLQEDLLRRFPDLNRLAKKFQRQAAN
LQDCYRLYQGINQLPNVIQALEKHEGKHQKLLLAVFVTPLTDLRSDFSKF
QEMIETTLDMDQVENHEFLVKPSFDPNLSELREIMNDLEKKMQSTLISAA
RDLGLDPGKQIKLDSSAQFGYYFRVTCKEEKVLRNNKNFSTVDIQKNGVK
FTNSKLTSLNEEYTKNKTEYEEAQDAIVKEIVNISSGYVEPMQTLNDVLA
QLDAVVSFAHVSNGAPVPYVRPAILEKGQGRIILKASRHACVEVQDEIAF
IPNDVYFEKDKQMFHIITGPNMGGKSTYIRQTGVIVLMAQIGCFVPCESA
EVSIVDCILARVGAGDSQLKGVSTFMAEMLETASILRSATKDSLIIIDEL
GRGTSTYDGFGLAWAISEYIATKIGAFCMFATHFHELTALANQIPTVNNL
HVTALTTEETLTMLYQVKKGVCDQSFGIHVAELANFPKHVIECAKQKALE
LEEFQYIGESQGYDIMEPAAKKCYLEREQGEKIIQEFLSKVKQMPFTEMS
EENITIKLKQLKAEVIAKNNSFVNEIISRIKVTT

Funkcija

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MSH2 je gen supresije tumora i preciznije domaćinski gen koji kodira protein za popravak neusklađenosti DNK (MMR), MSH2, koji formira heterodimer sa MSH6 da napravi kompleks za popravku neusklađenosti ljudskog MutSα. Takođe se dimerizira sa MSH3, kako bi formirao kompleks za popravku MutSβ DNK. MSH2 je uključen u mnogo različitih oblika popravka DNK, uključujući transkripcijski spregnuti popravak,[6] homologme rekombinacije,[7] i popravak eksicizujom baza.[8]

Klinički značaj

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Mutacije u genu MSH2 povezane su sa nestabilnošću mikrosatelita i nekim tipovima raka, posebno sa nasljednim nepolipnim kolorektumskim karcinomom (HNPCC).

Nasljedni nepolipasti kolorektalumskii karcinom, koji se ponekad naziva Lynchov sindrom, nasljeđuje se na autosomno dominantan način, gdje je nasljeđivanje samo jedne kopije mutiranog gena za popravak neusklađenosti dovoljno da izazove fenotip bolesti. Mutacije u genu MSH2 čine 40% genetićkih promjena povezanih s ovom bolešću i vodeći su uzrok, zajedno sa mutacijama MLH1.[9] Mutacije povezane sa HNPCC su široko rasprostranjene u svim domenima MSH2, a hipotetske funkcije ovih mutacija zasnovane na kristalnoj strukturi MutSα uključuju interakcije protein-protein, stabilnost, alosternu regulaciju, sučelje MSH2-MSH6 i DNK vezivanje.[10] Mutacije u MSH2 i drugim genima za popravku neusklađenosti uzrokuju da oštećenje DNK ostane nepopravljeno, što rezultira povećanjem učestalosti mutacija. Ove mutacije se nakupljaju tokom života osobe do kojih inače ne bi došlo da je DNK pravilno popravljena.

Nestabilnost mikrosatelita

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Vijabilnost MMR gena uključujući MSH2 može se pratiti putem mikrosatelitne nestabilnosti, testa biomarkera koji analizira ponavljanja kratkih sekvenci koje je ćelijama vrlo teško replicirati bez funkcionalnog sistema popravke neusklađenosti. Budući da ove sekvence variraju u populaciji, stvarni broj kopija kratkih ponavljanja sekvence nije bitan, samo je konzistentan broj koji pacijent ima od tkiva do tkiva i tokom vremena. Ovaj fenomen se javlja zato što su ove sekvence sklone greškama kompleksa replikacija DNK, koje onda treba popraviti genima za popravku neusklađenosti. Ako oni ne djeluju, s vremenom će doći do duplikacija ili delecija ovih sekvenci, što će dovesti do različitog broja ponavljanja kod istog pacijenta.

Oko 71% pacijenata sa HNPCC pokazuje mikrosatelitsku nestabilnost.|[11] Metodi detekcije nestabilnosti mikrosatelita uključuju lančanu reakciju polimeraze (PCR) i imunohistohemijske (IHC) metode, provjeru lanca polimeraze DNK i imunohistohemijsko ispitivanje nivoa proteina za popravku neusklađenosti. Sada postoje dokazi da je univerzalno testiranje za MSI počevši od IHC ili PCR baziranog MSI testiranja isplativo, osjetljivo, specifično i općenito je široko prihvaćeno.[12]

Uloga u popravku neusklađenosti

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Kod eukariota, od kvasaca do ljudi, MSH2 se dimerizira sa MSH6 kako bi formirao MutSα kompleks,[13] koji je uključen u popravku neusklađenosti baze i kratkih insercija/delecija petlje.[14] Heterodimerizacija MSH2 stabilizuje MSH6, koji nije stabilan zbog poremećenog N-terminalnog domena. Suprotno tome, MSH2 nema sekvencu jedarne lokalizacije (NLS), pa se vjeruje da MSH2 i MSH6 dimeriziraju u citoplazmi, a zatim se zajedno unose u ćelijsko jedro.[15] U dimeru MutSα, MSH6 stupa u interakciju sa DNK, radi prepoznavanja neusklađenosti, dok MSH2 pruža stabilnost koju MSH6 zahtijeva. MSH2 se može uvesti u jezgro bez dimerizacije u MSH6, a u ovom slučaju, MSH2 je vjerovatno dimeriziran u MSH3 da formira MutSβ.[16] MSH2 ima dva interakcijska domena sa MSH6 u heterodimeru MutSα, domen u interakciji DNK i domen ATPaze.[17]

MutSα dimer skenira dvolančanu DNK u jedru, tražeći neusklađene baze. Kada ga kompleks pronađe, popravlja mutaciju na način ovisan o ATP. MSH2 domen MutSα preferira ADP u odnosu na ATP, dok domen MSH6 preferira suprotno. Studije su pokazale da MutSα skenira samo DNK sa MSH2 domenom koja sadrži ADP, dok domen MSH6 može sadržavati ili ADP ili ATP.[18] MutSα se zatim povezuje sa MLH1 kako bi popravio oštećeni DNK.

MutSβ nastaje kada se MSH2 kompleksira sa MSH3 umjesto MSH6. Ovaj dimer popravlja duže petlje insercija/delecija od MutSα.[19] Zbog prirode mutacija koje ovaj kompleks popravlja, ovo je vjerovatno stanje MSH2 koje uzrokuje fenotip nestabilnosti mikrosatelita. Velike DNK insercije i delecije suštinski savijaju dvostruku spiralu DNK. MSH2/MSH3 dimer može prepoznati ovu topologiju i pokrenuti popravku. Mehanizam po kojem prepoznaje mutacije je također različit, jer razdvaja dva lanca DNK, što MutSα ne čini.[20]

Interakcije

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Pokazalo se da MSH2 međudjeluje sa:

Epigenetički nedostaci MSH2 kod kancera

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Oštećenje DNK je primarni uzrok raka,[33] a čini se da su nedostaci u ekspresiji gena za popravku DNK u osnovi mnogih oblika raka.[34][35] Ako je popravka DNK manjkava, oštećenje DNK ima tendenciju da se akumulira. Takvo prekomjerno oštećenje DNK može povećati mutacije zbog sklone greškama sinteze translezija i popravke sklone greškama. Povećano oštećenje DNK također može povećati epigenetičke promjene zbog grešaka tokom popravke DNK.[36][37] Takve mutacije i epigenetičke promjene mogu dovesti do kancera.

Smanjenje ekspresije gena za popravku DNK (obično uzrokovano epigenetičkim promjenama) vrlo je uobičajeno kod karcinoma i obično je mnogo češće od mutacijskih defekata u genima za popravku DNK kod karcinoma. U studiji o MSH2 u karcinom plućnih nemalih ćelija (NSCLC), mutacije nisu pronađene dok je 29% imalo epigenetičku redukciju ekspresije "MSH2".[38] U akutnoj limfoblastoidna leukemiji (ALL), nisu pronađene mutacije MSH2 [39] dok je 43% pacijenata sa ALL pokazalo metilaciju promotora MSH2, a njih 86% pacijenata sa relapsom imalo je metilaciju promotora MSH2.[40] Postojale su, međutim, mutacije u četiri druga gena kod ALL pacijenata koje su destabilizirale protein MSH2, a one su bile defektne kod 11% djece sa ALL i 16% odraslih s ovim karcinomom.[39]

Metilacija promotorske regije gena "MSH2" je u korelaciji sa nedostatkom ekspresije proteina MSH2 kod raka jednjaka,[41] u karcinom nemalih ćelija pluća,[38][42] i kolorektumskom kanceru.[43] Ove korelacije sugeriraju da metilacija promotorske regije gena "MSH2" smanjuje ekspresiju MSH2 proteina. Takva metilacija promotora bi smanjila popravak DNK na četiri puta u kojima učestvuje MSH2: popravak neslaganja DNK, popravak vezan uz transkripciju[6] homologna rekombinacija,[7][44][45] i popravak ekscizijom baza.[8] Takva smanjenja u popravci vjerovatno omogućavaju da se višak oštećenja DNK akumulira i doprinosi karcinogenezi.

Učestalosti metilacije promotora MSH2 u nekoliko različitih karcinoma prikazane su u tabeli.

MSH2 promotor metilacije kod sporadičnih karcinoma
Kancer Učestalost metilacije promotora MSH2 Referenca
Akutna limfoblastna leukemija 43% [40]
Povratna Akutna limfoblastna leukemija 86% [40]
Karcinom bubrežnih ćelija 51–55% [46][47]
Karcinom jednjačkih pločastih ćelija 29–48% [41][48]
Karcinom pločastih ćelija glave i vrata 27–36% [49][50][51]
Karcinom plućnih nemalih ćelia 29–34% [38][42]
Hepatoćelijski karcinom 10–29% [52]
Kolorektumski kancer 3–24% [43][53][54][55]
Sarkom mehkog tkiva 8% [56]

Također pogledajte

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Reference

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