MSH2

MSH2
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 2O8B, 2O8C, 2O8D, 2O8E, 2O8F, 3THW, 3THX, 3THY, 3THZ
Identifikatori
Aliasi	MSH2
Vanjski ID-jevi	OMIM: 609309 MGI: 101816 HomoloGene: 210 GeneCards: MSH2
Lokacija gena (čovjek) Hrom. Hromosom 2 (čovjek)[1] Bend 2p21-p16.3 Početak 47,403,067 bp[1] Kraj 47,663,146 bp[1]
Lokacija gena (miš) Hrom. Hromosom 17 (miš)[2] Bend 17 E4|17 57.87 cM Početak 87,979,758 bp[2] Kraj 88,031,141 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
Vrste	Čovjek	Miš
Entrez	4436	17685
Ensembl	ENSG00000095002	ENSMUSG00000024151
UniProt	P43246	P43247
RefSeq (mRNK)	NM_000251 NM_001258281	NM_008628
RefSeq (bjelančevina)	NP_000242 NP_001245210	NP_032654
Lokacija (UCSC)	Chr 2: 47.4 – 47.66 Mb	Chr 17: 87.98 – 88.03 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/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

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

• 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
MAVQPKETLQ		LESAAEVGFV		RFFQGMPEKP		TTTVRLFDRG		DFYTAHGEDA
LLAAREVFKT		QGVIKYMGPA		GAKNLQSVVL		SKMNFESFVK		DLLLVRQYRV
EVYKNRAGNK		ASKENDWYLA		YKASPGNLSQ		FEDILFGNND		MSASIGVVGV
KMSAVDGQRQ		VGVGYVDSIQ		RKLGLCEFPD		NDQFSNLEAL		LIQIGPKECV
LPGGETAGDM		GKLRQIIQRG		GILITERKKA		DFSTKDIYQD		LNRLLKGKKG
EQMNSAVLPE		MENQVAVSSL		SAVIKFLELL		SDDSNFGQFE		LTTFDFSQYM
KLDIAAVRAL		NLFQGSVEDT		TGSQSLAALL		NKCKTPQGQR		LVNQWIKQPL
MDKNRIEERL		NLVEAFVEDA		ELRQTLQEDL		LRRFPDLNRL		AKKFQRQAAN
LQDCYRLYQG		INQLPNVIQA		LEKHEGKHQK		LLLAVFVTPL		TDLRSDFSKF
QEMIETTLDM		DQVENHEFLV		KPSFDPNLSE		LREIMNDLEK		KMQSTLISAA
RDLGLDPGKQ		IKLDSSAQFG		YYFRVTCKEE		KVLRNNKNFS		TVDIQKNGVK
FTNSKLTSLN		EEYTKNKTEY		EEAQDAIVKE		IVNISSGYVE		PMQTLNDVLA
QLDAVVSFAH		VSNGAPVPYV		RPAILEKGQG		RIILKASRHA		CVEVQDEIAF
IPNDVYFEKD		KQMFHIITGP		NMGGKSTYIR		QTGVIVLMAQ		IGCFVPCESA
EVSIVDCILA		RVGAGDSQLK		GVSTFMAEML		ETASILRSAT		KDSLIIIDEL
GRGTSTYDGF		GLAWAISEYI		ATKIGAFCMF		ATHFHELTAL		ANQIPTVNNL
HVTALTTEET		LTMLYQVKKG		VCDQSFGIHV		AELANFPKHV		IECAKQKALE
LEEFQYIGES		QGYDIMEPAA		KKCYLEREQG		EKIIQEFLSK		VKQMPFTEMS
EENITIKLKQ		LKAEVIAKNN		SFVNEIISRI		KVTT

Funkcija

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

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

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

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

Pokazalo se da MSH2 međudjeluje sa:

• ATR,^[21][22]
• BRCA1,^[23]
• CHEK2,^[24][25]
• EXO1,^[26][27][28]
• MAX,^[29]
• MSH3,^{[17][21][30][31]}
• MSH6,^{[17][21][23][30][31]} i
• p53.^[32]

Epigenetički nedostaci MSH2 kod kancera

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

• Popravak DNK

Reference

1. GRCh38: Ensembl release 89: ENSG00000095002 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024151 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "UniProt, P43246" (jezik: engleski). Pristupljeno 13. 11. 2021.
6. Mellon I, Rajpal DK, Koi M, Boland CR, Champe GN (april 1996). "Transcription-coupled repair deficiency and mutations in human mismatch repair genes". Science. 272 (5261): 557–60. Bibcode:1996Sci...272..557M. doi:10.1126/science.272.5261.557. PMID 8614807. S2CID 13084965.
7. de Wind N, Dekker M, Berns A, Radman M, te Riele H (juli 1995). "Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer". Cell. 82 (2): 321–30. doi:10.1016/0092-8674(95)90319-4. PMID 7628020. S2CID 7954019.
8. Pitsikas P, Lee D, Rainbow AJ (maj 2007). "Reduced host cell reactivation of oxidative DNA damage in human cells deficient in the mismatch repair gene hMSH2". Mutagenesis. 22 (3): 235–43. doi:10.1093/mutage/gem008. PMID 17351251.
9. Müller A, Fishel R (2002). "Mismatch repair and the hereditary non-polyposis colorectal cancer syndrome (HNPCC)". Cancer Invest. 20 (1): 102–9. doi:10.1081/cnv-120000371. PMID 11852992. S2CID 3581304.
10. Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS (maj 2007). "Structure of the human MutSalpha DNA lesion recognition complex". Mol. Cell. 26 (4): 579–92. doi:10.1016/j.molcel.2007.04.018. PMID 17531815.
11. Bonis PA, Trikalinos TA, Chung M, Chew P, Ip S, DeVine DA, Lau J (maj 2007). "Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications". Evid Rep Technol Assess (Full Rep) (150): 1–180. PMC 4781224. PMID 17764220.
12. Zhang X, Li J (februar 2013). "Era of universal testing of microsatellite instability in colorectal cancer". World J Gastrointest Oncol. 5 (2): 12–9. doi:10.4251/wjgo.v5.i2.12. PMC 3613766. PMID 23556052.
13. Hargreaves VV, Shell SS, Mazur DJ, Hess MT, Kolodner RD (mart 2010). "Interaction between the Msh2 and Msh6 nucleotide-binding sites in the Saccharomyces cerevisiae Msh2-Msh6 complex". J. Biol. Chem. 285 (12): 9301–10. doi:10.1074/jbc.M109.096388. PMC 2838348. PMID 20089866.
14. Drummond JT, Li GM, Longley MJ, Modrich P (juni 1995). "Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells". Science. 268 (5219): 1909–12. Bibcode:1995Sci...268.1909D. doi:10.1126/science.7604264. PMID 7604264.
15. Christmann M, Kaina B (novembar 2000). "Nuclear translocation of mismatch repair proteins MSH2 and MSH6 as a response of cells to alkylating agents". J. Biol. Chem. 275 (46): 36256–62. doi:10.1074/jbc.M005377200. PMID 10954713.
16. Edelbrock MA, Kaliyaperumal S, Williams KJ (februar 2013). "Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities". Mutat. Res. 743–744: 53–66. doi:10.1016/j.mrfmmm.2012.12.008. PMC 3659183. PMID 23391514.
17. Guerrette S, Wilson T, Gradia S, Fishel R (novembar 1998). "Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer". Mol. Cell. Biol. 18 (11): 6616–23. doi:10.1128/mcb.18.11.6616. PMC 109246. PMID 9774676.
18. Qiu R, DeRocco VC, Harris C, Sharma A, Hingorani MM, Erie DA, Weninger KR (maj 2012). "Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling". EMBO J. 31 (11): 2528–40. doi:10.1038/emboj.2012.95. PMC 3365432. PMID 22505031.
19. Dowen JM, Putnam CD, Kolodner RD (juli 2010). "Functional studies and homology modeling of Msh2-Msh3 predict that mispair recognition involves DNA bending and strand separation". Mol. Cell. Biol. 30 (13): 3321–8. doi:10.1128/MCB.01558-09. PMC 2897569. PMID 20421420.
20. Gupta S, Gellert M, Yang W (januar 2012). "Mechanism of mismatch recognition revealed by human MutSβ bound to unpaired DNA loops". Nat. Struct. Mol. Biol. 19 (1): 72–8. doi:10.1038/nsmb.2175. PMC 3252464. PMID 22179786.
21. Wang Y, Qin J (decembar 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proc. Natl. Acad. Sci. U.S.A. 100 (26): 15387–92. Bibcode:2003PNAS..10015387W. doi:10.1073/pnas.2536810100. PMC 307577. PMID 14657349.
22. Wang Q, Zhang H, Guerrette S, Chen J, Mazurek A, Wilson T, Slupianek A, Skorski T, Fishel R, Greene MI (august 2001). "Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1". Oncogene. 20 (34): 4640–9. doi:10.1038/sj.onc.1204625. PMID 11498787.
23. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (april 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. doi:10.1101/gad.14.8.927 (neaktivno 31. 10. 2021). PMC 316544. PMID 10783165.
24. Adamson AW, Beardsley DI, Kim WJ, Gao Y, Baskaran R, Brown KD (mart 2005). "Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2". Mol. Biol. Cell. 16 (3): 1513–26. doi:10.1091/mbc.E04-02-0089. PMC 551512. PMID 15647386.
25. Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (januar 2003). "The mismatch repair system is required for S-phase checkpoint activation". Nat. Genet. 33 (1): 80–4. doi:10.1038/ng1052. PMID 12447371. S2CID 20616220.
26. Rasmussen LJ, Rasmussen M, Lee B, Rasmussen AK, Wilson DM, Nielsen FC, Bisgaard HC (juni 2000). "Identification of factors interacting with hMSH2 in the fetal liver utilizing the yeast two-hybrid system. In vivo interaction through the C-terminal domains of hEXO1 and hMSH2 and comparative expression analysis". Mutat. Res. 460 (1): 41–52. doi:10.1016/S0921-8777(00)00012-4. PMID 10856833.
27. Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fishel R (oktobar 1998). "Human exonuclease I interacts with the mismatch repair protein hMSH2". Cancer Res. 58 (20): 4537–42. PMID 9788596.
28. Schmutte C, Sadoff MM, Shim KS, Acharya S, Fishel R (august 2001). "The interaction of DNA mismatch repair proteins with human exonuclease I". J. Biol. Chem. 276 (35): 33011–8. doi:10.1074/jbc.M102670200. PMID 11427529.
29. Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST, Matheson EC, Hall AG, Gillespie DA, Brown R (februar 2003). "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene. 22 (6): 819–25. doi:10.1038/sj.onc.1206252. PMID 12584560.
30. Bocker T, Barusevicius A, Snowden T, Rasio D, Guerrette S, Robbins D, Schmidt C, Burczak J, Croce CM, Copeland T, Kovatich AJ, Fishel R (februar 1999). "hMSH5: a human MutS homologue that forms a novel heterodimer with hMSH4 and is expressed during spermatogenesis". Cancer Res. 59 (4): 816–22. PMID 10029069.
31. Acharya S, Wilson T, Gradia S, Kane MF, Guerrette S, Marsischky GT, Kolodner R, Fishel R (novembar 1996). "hMSH2 forms specific mispair-binding complexes with hMSH3 and hMSH6". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 13629–34. Bibcode:1996PNAS...9313629A. doi:10.1073/pnas.93.24.13629. PMC 19374. PMID 8942985.
32. Scherer SJ, Welter C, Zang KD, Dooley S (april 1996). "Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2". Biochem. Biophys. Res. Commun. 221 (3): 722–8. doi:10.1006/bbrc.1996.0663. PMID 8630028.
33. Kastan MB (april 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
34. Harper JW, Elledge SJ (decembar 2007). "The DNA damage response: ten years after". Molecular Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
35. Dietlein F, Reinhardt HC (decembar 2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clinical Cancer Research. 20 (23): 5882–7. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105.
36. O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLOS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
37. Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (juli 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
38. Wang YC, Lu YP, Tseng RC, Lin RK, Chang JW, Chen JT, Shih CM, Chen CY (2003). "Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples". J. Clin. Invest. 111 (6): 887–95. doi:10.1172/JCI15475. PMC 153761. PMID 12639995.
39. Diouf B, Cheng Q, Krynetskaia NF, Yang W, Cheok M, Pei D, Fan Y, Cheng C, Krynetskiy EY, Geng H, Chen S, Thierfelder WE, Mullighan CG, Downing JR, Hsieh P, Pui CH, Relling MV, Evans WE (2011). "Somatic deletions of genes regulating MSH2 protein stability cause DNA mismatch repair deficiency and drug resistance in human leukemia cells". Nat. Med. 17 (10): 1298–303. doi:10.1038/nm.2430. PMC 3192247. PMID 21946537.
40. Wang CX, Wang X, Liu HB, Zhou ZH (2014). "Aberrant DNA methylation and epigenetic inactivation of hMSH2 decrease overall survival of acute lymphoblastic leukemia patients via modulating cell cycle and apoptosis". Asian Pac. J. Cancer Prev. 15 (1): 355–62. doi:10.7314/apjcp.2014.15.1.355. PMID 24528056.
41. Ling ZQ, Li P, Ge MH, Hu FJ, Fang XH, Dong ZM, Mao WM (2011). "Aberrant methylation of different DNA repair genes demonstrates distinct prognostic value for esophageal cancer". Dig. Dis. Sci. 56 (10): 2992–3004. doi:10.1007/s10620-011-1774-z. PMID 21674174. S2CID 22913110.
42. Hsu HS, Wen CK, Tang YA, Lin RK, Li WY, Hsu WH, Wang YC (2005). "Promoter hypermethylation is the predominant mechanism in hMLH1 and hMSH2 deregulation and is a poor prognostic factor in nonsmoking lung cancer". Clin. Cancer Res. 11 (15): 5410–6. doi:10.1158/1078-0432.CCR-05-0601. PMID 16061855.
43. Lee KH, Lee JS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Lee JH (2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbecks Arch Surg. 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233. S2CID 8069716.
44. Villemure JF, Abaji C, Cousineau I, Belmaaza A (2003). "MSH2-deficient human cells exhibit a defect in the accurate termination of homology-directed repair of DNA double-strand breaks". Cancer Res. 63 (12): 3334–9. PMID 12810667.
45. Elliott B, Jasin M (2001). "Repair of double-strand breaks by homologous recombination in mismatch repair-defective mammalian cells". Mol. Cell. Biol. 21 (8): 2671–82. doi:10.1128/MCB.21.8.2671-2682.2001. PMC 86898. PMID 11283247.
46. Stoehr C, Burger M, Stoehr R, Bertz S, Ruemmele P, Hofstaedter F, Denzinger S, Wieland WF, Hartmann A, Walter B (2012). "Mismatch repair proteins hMLH1 and hMSH2 are differently expressed in the three main subtypes of sporadic renal cell carcinoma" (PDF). Pathobiology. 79 (3): 162–8. doi:10.1159/000335642. PMID 22378480. S2CID 26687941.
47. Yoo KH, Won KY, Lim SJ, Park YK, Chang SG (2014). "Deficiency of MSH2 expression is associated with clear cell renal cell carcinoma". Oncol Lett. 8 (5): 2135–2139. doi:10.3892/ol.2014.2482. PMC 4186615. PMID 25295100.
48. Ling ZQ, Zhao Q, Zhou SL, Mao WM (2012). "MSH2 promoter hypermethylation in circulating tumor DNA is a valuable predictor of disease-free survival for patients with esophageal squamous cell carcinoma". Eur J Surg Oncol. 38 (4): 326–32. doi:10.1016/j.ejso.2012.01.008. PMID 22265839.
49. Sengupta S, Chakrabarti S, Roy A, Panda CK, Roychoudhury S (2007). "Inactivation of human mutL homolog 1 and mutS homolog 2 genes in head and neck squamous cell carcinoma tumors and leukoplakia samples by promoter hypermethylation and its relation with microsatellite instability phenotype". Cancer. 109 (4): 703–12. doi:10.1002/cncr.22430. PMID 17219447. S2CID 20191692.
50. Demokan S, Suoglu Y, Demir D, Gozeler M, Dalay N (2006). "Microsatellite instability and methylation of the DNA mismatch repair genes in head and neck cancer". Ann. Oncol. 17 (6): 995–9. doi:10.1093/annonc/mdl048. PMID 16569647.
51. Czerninski R, Krichevsky S, Ashhab Y, Gazit D, Patel V, Ben-Yehuda D (2009). "Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2 in oral squamous cell carcinoma". Oral Dis. 15 (3): 206–13. doi:10.1111/j.1601-0825.2008.01510.x. PMID 19207881.
52. Hinrichsen I, Kemp M, Peveling-Oberhag J, Passmann S, Plotz G, Zeuzem S, Brieger A (2014). "Promoter methylation of MLH1, PMS2, MSH2 and p16 is a phenomenon of advanced-stage HCCs". PLOS ONE. 9 (1): e84453. Bibcode:2014PLoSO...984453H. doi:10.1371/journal.pone.0084453. PMC 3882222. PMID 24400091.
53. Vlaykova T, Mitkova A, Stancheva G, Kadiyska T, Gulubova M, Yovchev Y, Cirovski G, Chilingirov P, Damyanov D, Kremensky I, Mitev V, Kaneva R (2011). "Microsatellite instability and promoter hypermethylation of MLH1 and MSH2 in patients with sporadic colorectal cancer". J BUON. 16 (2): 265–73. PMID 21766496.
54. Malhotra P, Anwar M, Kochhar R, Ahmad S, Vaiphei K, Mahmood S (2014). "Promoter methylation and immunohistochemical expression of hMLH1 and hMSH2 in sporadic colorectal cancer: a study from India". Tumour Biol. 35 (4): 3679–87. doi:10.1007/s13277-013-1487-3. PMID 24317816. S2CID 10615946.
55. Onrat S, Ceken I, Ellidokuz E, Kupelioğlu A (2011). "Alterations of copy number of methylation pattern in mismatch repair genes by methylation specific-multiplex ligation-dependent probe amplification in cases of colon cancer". Balkan J. Med. Genet. 14 (2): 25–34. doi:10.2478/v10034-011-0044-x. PMC 3776700. PMID 24052709.
56. Kawaguchi K, Oda Y, Saito T, Yamamoto H, Takahira T, Kobayashi C, Tamiya S, Tateishi N, Iwamoto Y, Tsuneyoshi M (2006). "DNA hypermethylation status of multiple genes in soft tissue sarcomas". Mod. Pathol. 19 (1): 106–14. doi:10.1038/modpathol.3800502. PMID 16258501.

Dopunska literatura

• Jiricny J (1994). "Colon cancer and DNA repair: have mismatches met their match?". Trends Genet. 10 (5): 164–8. doi:10.1016/0168-9525(94)90093-0. PMID 8036718.
• Fishel R, Wilson T (1997). "MutS homologs in mammalian cells". Curr. Opin. Genet. Dev. 7 (1): 105–13. doi:10.1016/S0959-437X(97)80117-7. PMID 9024626.
• Lothe RA (1997). "Microsatellite instability in human solid tumors". Molecular Medicine Today. 3 (2): 61–8. doi:10.1016/S1357-4310(96)10055-1. PMID 9060003.
• Peltomäki P, de la Chapelle A (1997). "Mutations predisposing to hereditary nonpolyposis colorectal cancer". Adv. Cancer Res. Advances in Cancer Research. 71: 93–119. doi:10.1016/S0065-230X(08)60097-4. ISBN 9780120066711. PMID 9111864.
• Papadopoulos N, Lindblom A (1997). "Molecular basis of HNPCC: mutations of MMR genes". Hum. Mutat. 10 (2): 89–99. doi:10.1002/(SICI)1098-1004(1997)10:2<89::AID-HUMU1>3.0.CO;2-H. PMID 9259192.
• Kauh J, Umbreit J (2004). "Colorectal cancer prevention". Current Problems in Cancer. 28 (5): 240–64. doi:10.1016/j.currproblcancer.2004.05.004. PMID 15375803.
• Warusavitarne J, Schnitzler M (2007). "The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer". International Journal of Colorectal Disease. 22 (7): 739–48. doi:10.1007/s00384-006-0228-0. PMID 17109103. S2CID 6460105.
• Wei Q, Xu X, Cheng L, et al. (1995). "Simultaneous amplification of four DNA repair genes and beta-actin in human lymphocytes by multiplex reverse transcriptase-PCR". Cancer Res. 55 (21): 5025–9. PMID 7585546.
• Wilson TM, Ewel A, Duguid JR, et al. (1995). "Differential cellular expression of the human MSH2 repair enzyme in small and large intestine". Cancer Res. 55 (22): 5146–50. PMID 7585562.
• Drummond JT, Li GM, Longley MJ, Modrich P (1995). "Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch repair to tumor cells". Science. 268 (5219): 1909–12. Bibcode:1995Sci...268.1909D. doi:10.1126/science.7604264. PMID 7604264.
• Kolodner RD, Hall NR, Lipford J, et al. (1995). "Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations". Genomics. 24 (3): 516–26. doi:10.1006/geno.1994.1661. PMID 7713503.
• Wijnen J, Vasen H, Khan PM, et al. (1995). "Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis". Am. J. Hum. Genet. 56 (5): 1060–6. PMC 1801472. PMID 7726159.
• Mary JL, Bishop T, Kolodner R, et al. (1995). "Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development". Hum. Mol. Genet. 3 (11): 2067–9. PMID 7874129.
• Fishel R, Ewel A, Lescoe MK (1994). "Purified human MSH2 protein binds to DNA containing mismatched nucleotides". Cancer Res. 54 (21): 5539–42. PMID 7923193.
• Fishel R, Ewel A, Lee S, et al. (1994). "Binding of mismatched microsatellite DNA sequences by the human MSH2 protein". Science. 266 (5189): 1403–5. Bibcode:1994Sci...266.1403F. doi:10.1126/science.7973733. PMID 7973733.
• Liu B, Parsons RE, Hamilton SR, et al. (1994). "hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds". Cancer Res. 54 (17): 4590–4. PMID 8062247.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Fishel R, Lescoe MK, Rao MR, et al. (1994). "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer". Cell. 77 (1): 167–169. doi:10.1016/0092-8674(94)90306-9. PMID 8156592. S2CID 45905483.
• Fishel R, Lescoe MK, Rao MR, et al. (1994). "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer". Cell. 75 (5): 1027–38. doi:10.1016/0092-8674(93)90546-3. PMID 8252616.

Vanjski linkovi

• MutS Homolog 2 Protein na US National Library of Medicine Medical Subject Headings (MeSH)