ライフサイエンスコーパス: MSH2

1 in mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2).

2 ance (VUS), focusing on mutator S homolog 2 (MSH2).

3 trolling the DNA mismatch repair function of MSH2.

4 and histone deacetylase (HDAC6) deacetylates MSH2.

5 mainly as a result of mutations in MLH1 and MSH2.

6 of the upstream mismatch recognition factor MSH2.

7 match repair activities by downregulation of MSH2.

8 se mutation in the mismatch repair component MSH2.

9 chanisms of somatic inactivation of MLH1 and MSH2.

10 ypes can be rescued by ectopic expression of MSH2.

11 in an UNG-dependent manner but are offset by MSH2.

12 ase 10 (USP10) interacts with and stabilizes MSH2.

13 ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53.

14 e with constitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 pa

15 he MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutat

16 ed with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH

17 ency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%).

18 Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early

19 ly unrecognized consequence of deficiency in MSH2, a protein known primarily for its function in corr

20 Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for as

21 We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were

22 The MSH2 A636P mutation is a founder mutation in Ashkenazi J

23 Deleterious mutations in human MSH2 account for approximately half of the alleles assoc

24 odels for MMR, and may partially explain the MSH2 allele frequency in Lynch syndrome or hereditary no

25 t simultaneous deficiency of UNG and MSH2 or MSH2 alone causes genomic instability and a shorter late

26 unohistochemical analyses were performed for MSH2, along with allele-specific PCR assays.

27 polymerase kappa (Polkappa) can partner with MSH2, an important mismatch repair protein associated wi

28 2dC significantly restored the expression of MSH2 and doxorubicin-induced cytotoxicity in Caki-1 cell

29 Both MSH2 and MLH1 are required for efficient replication of

30 Surprisingly, the interaction between MSH2 and MLH1 is compromised in multiple FA cell lines,

31 st an epistatic relationship between FANCD2, MSH2 and MLH1 with regard to ICL repair.

32 that FANCD2 interacts with the MMR proteins MSH2 and MLH1.

33 Ectopic expression of MSH2 and MSH3 induced GAA.TTC repeat expansion in the na

34 , ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems.

35 MutSbeta, a heterodimer of MSH2 and MSH3, is known to have a role in CAG.CTG repeat

36 ease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on temozolomide sens

37 In addition, shRNA silencing of MSH2 and MSH6 impeded GAA.TTC triplet-repeat expansion.

38 RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided

39 ss of staining for the mismatch repair genes MSH2 and MSH6.

40 ors insulate MMR from defects in domain I of Msh2 and provide insights into how mutations in Msh2 dom

41 get genes in the combined absence of UNG and MSH2 and that DNA strand lesions arise in an UNG-depende

42 Patients with MSI and loss of MSH2 and/or MSH6 expression, isolated loss of PMS2 or lo

43 g similar to that found in MutS homologue 2 (Msh2)- and Mlh1-deficient B cells.

44 downstream targets IKBKB, WEE1, FGF2, RAD50, MSH2, and KIT.

45 were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 prom

46 ates that this HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with

47 Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite inst

48 in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6.

49 ons in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6.

50 erference screens using tumor cell models of MSH2- and MLH1-related MMR deficiency.

51 Silencing of MSH2 appears to inhibit early gene expression.

52 Our results show that MLH1, EXO1, and MSH2 are all important for efficient A-EJ-mediated CSR,

53 Abnormal IHC results, including absence of MSH2, are not diagnostic of LS and should be interpreted

54 HDAC10 is the major enzyme that deacetylates MSH2 at Lys-73.

55 ur results highlight the powerful effects of MSH2 attenuation as a potent mediator of temozolomide re

56 Here, we show that MSH3, the MSH2-binding partner in the MutSbeta complex, is require

57 p21 degradation further required MSH2 but not MLH1.

58 sis catalog for the MMR gene MutS Homolog 2 (Msh2) by mutagenizing, identifying, and cataloging 26 de

59 However, whether other regions of MSH2 can be acetylated and whether other histone deacety

60 Here, we report that MSH2 can be acetylated at Lys-73 near the N terminus.

61 We created mice in which the MMR gene Msh2 can be inactivated in a defined fraction of crypt b

62 Moreover, we observed that MSH2 can facilitate TLS across cyclobutane pyrimidine di

63 in PCNA monoubiquitination, indicating that MSH2 can regulate post-UV focus formation by specialized

64 Mutation or dysregulation of MSH2 causes genomic instability that can lead to cancer.

65 vity, because DeltaAID is not a DN mutant in msh2(-/-) cells.

66 Ung(-/-), Msh2(-/-), Msh6(-/-), and Ung(-/-) Msh2(-/-) clones suggest that pol zeta may function in t

67 as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells.

68 Leukemia cells with low levels of MSH2 contained partial or complete somatic deletions of

69 enes, 17 of which, including TCF7L2, TWIST2, MSH2, DCC, EPHB1 and EPHB2 have been previously implicat

70 ne acetyltransferases (HATs) are involved in MSH2 deacetylation/acetylation is unknown.

71 In addition, knockdown of MSH2 decreases the cellular mismatch repair activity.

72 We anticipate that identifying MSH2 defects in infecting strains may influence the mana

73 We documented that Msh2 deficiency causes dysmyelination of the axonal proj

74 ngs reveal a novel pathogenic consequence of MSH2 deficiency, providing a new mechanistic hint to pre

75 arcinomas than control mice; all tumors were MSH2 deficient.

76 chromatin loading are greatly diminished in MSH2-deficient cells.

77 We traced the fate of MSH2-deficient crypts under the influence of different e

78 f crypt base columnar stem cells to generate MSH2-deficient intestinal crypts among an excess of wild

79 to the methylating agent temozolomide caused MSH2-deficient intestinal stem cells to proliferate more

80 The MSH2-deficient intestinal stem cells were able to coloni

81 wing decreased S-junction microhomologies in MSH2-deficient mice and an exonuclease 1 (EXO1) role in

82 In 13 of 25 tumors (8 MLH1-deficient and 5 MSH2-deficient tumors), we identified 2 somatic mutation

83 deletions of one to four genes that regulate MSH2 degradation (FRAP1 (also known as MTOR), HERC1, PRK

84 hereby somatic deletions of genes regulating MSH2 degradation result in undetectable levels of MSH2 p

85 ted the MSH2 protein deficiency by enhancing MSH2 degradation, leading to substantial reduction in DN

86 cetylates and ubiquitinates MSH2, leading to MSH2 degradation.

87 Thus, we propose that regulation of MSH2-dependent DNA damage response underlies the importa

88 inal binding protein interacting protein and MSH2-dependent DSB repair during CSR.

89 terminal binding protein interacting protein/MSH2-dependent pathway that relies on microhomology can

90 el function for MLH1 distinct from its known MSH2-dependent role in mismatch repair.

91 MSH2 depletion also suppresses ICL sensitivity in cells

92 MSH2 depletion suppresses an aberrant DNA damage respons

93 Therefore, the level of MSH2 determines DNA damage response.

94 Loss of MSH2 did not correlate with age.

95 ants interacted with San1, whereas wild-type Msh2 did not.

96 ologous 3' tail, the mismatch repair protein Msh2 does not discourage homeologous recombination.

97 eletes the conserved DNA-binding domain I of Msh2, does not dramatically affect Msh2-Msh6-dependent r

98 To understand the role of Msh2 domain I in MMR, we examined the consequences of co

99 2 and provide insights into how mutations in Msh2 domain I may cause hereditary non-polyposis colorec

100 carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifun

101 e of DNA hypermethylation in inactivation of MSH2 expression and consequently MMR-dependent apoptosis

102 Lgr5-CreERT2;Msh2(flox/-) mice developed more adenomas and adenocarci

103 Exposure of Lgr5-CreERT2;Msh2(flox/-) mice to the methylating agent temozolomide

104 mouse model of Lynch syndrome (Lgr5-CreERT2;Msh2(flox/-) mice) and found that environmental factors

105 an excess of wild-type crypts (Lgr5-CreERT2;Msh2(flox/-) mice).

106 MSH3, together with MSH2, forms the MutSbeta heteroduplex, which interacts w

107 Loss or depletion of MSH2 from cells renders resistance to certain DNA-damagi

108 ially blocked repeat expansion by displacing MSH2 from FXN intron 1 in FRDA iPSCs.

109 t interaction with MLH1, and the MMR protein MSH2 function in a common pathway in response to UV irra

110 Msh2(G674A) or Msh6(T1217D) mice that have mutations in

111 Mutant human MutSalpha proteins MSH2(G674A)-MSH6(wt) and MSH2(wt)-MSH6(T1219D) are profi

112 de binding and mismatch recognition, whereas MSH2(G674A)-MSH6(wt) has a partial defect in nucleotide

113 VUS were introduced into the endogenous Msh2 gene of mouse embryonic stem cells by oligo targeti

114 among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44-56.5).

115 h several Class I and II HDACs interact with MSH2, HDAC10 is the major enzyme that deacetylates MSH2

116 We found that depletion of MSH2 impairs PCNA monoubiquitination and the formation o

117 In addition, shRNA silencing of MSH2 impeded CTG.CAG triplet-repeat expansion.

118 sed expression of mismatch repair (MMR) gene MSH2 in cells exposed to oxidative stress suggests that

119 in living cells, presenting a novel role of MSH2 in post-UV cellular responses.

120 Interestingly, expression of MSH2 in Rad18-deficient cells increased UV-induced Polka

121 USP10 deubiquitinates MSH2 in vitro and in vivo Moreover, the protein level of

122 utL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in HPCs and colony-forming cell-derived clones (CF

123 We show that MSH2 interacts with FEN1 and facilitates its nuclease ac

124 MSH2 is a key DNA mismatch repair protein, which plays a

125 MSH2 is acetylated at its C terminus, and histone deacet

126 MSH2 is central to mismatch repair and its absence or re

127 ite its essential role in GAA.TTC expansion, MSH2 is not an attractive therapeutic target.

128 o and in vivo Moreover, the protein level of MSH2 is positively correlated with the USP10 protein lev

129 MSH2 is required for DNA mismatch repair recognition in

130 rated that the mismatch repair (MMR) protein MSH2 is required for expansions in a mouse model of thes

131 in S regions, and we find in this study that Msh2 is required for the DN activity, because DeltaAID i

132 an earlier role in HSV-1 infection than does MSH2 is surprising and may indicate a novel function for

133 MutS protein homolog 2 (MSH2) is a key DNA mismatch repair protein.

134 MutS homolog 2 (MSH2) is an essential DNA mismatch repair (MMR) protein.

135 s), DNA repair/replication processes (PARP1, MSH2, Ku, DNA-PKcs, MCM proteins, PCNA and DNA Pol delta

136 sequentially deacetylates and ubiquitinates MSH2, leading to MSH2 degradation.

137 t one variant, but did not elevate wild-type Msh2 levels.

138 Rescue by Msh2 loss was confirmed in Fancd2-null primary mouse cel

139 DNA mismatch repair enzymes (for example, MSH2) maintain genomic integrity, and their deficiency p

140 lase (UNG)-mediated base-excision repair and MSH2-mediated mismatch repair (MMR) to yield mutations a

141 Observations in Ung(-/-) Msh2(-/-) mice suggest that many other genes efficiently

142 UNG exacerbates the cancer predisposition of Msh2(-/-) mice suggesting that when both base excision a

143 egulatory context, from 83 genes in Ung(-/-) Msh2(-/-) mice to identify common properties of AID targ

144 robiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates

145 PCNA, the MSH2 mismatch repair protein and the XPA nucleotide exci

146 usly, we characterized clinically identified MSH2 missense mutations, using yeast as a model system,

147 lymerase-delta, although the repair proteins Msh2, Mlh1 and Exo1 influence the extent of correction.

148 ations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively.

149 lly lethal with MMR deficiency in cells with MSH2, MLH1, or MSH6 dysfunction.

150 genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of ge

151 ation of the DNA mismatch repair genes MLH1, MSH2, MLH3, MSH6, PMS2, MGMT and MLH3 via methylation sp

152 nstitutional MLH1 methylation]; 16, MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had

153 2 protein levels, despite abundant wild-type MSH2 mRNA.

154 The mismatch repair components MSH2, MSH3 and MSH6 were highly expressed in iPSCs compa

155 The mismatch repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability i

156 It forms the MSH2-MSH6 (MutSalpha) and MSH2-MSH3 (MutSbeta) heterodimers, which help to ensure

157 In the other, Msh2-Msh6 or Msh2-Msh3 activate the MutL homolog 1 (Mlh1)-postmeiotic

158 h2-Msh3 and performed a comparative study of Msh2-Msh3 and Msh2-Msh6 for mispair binding, sliding cla

159 Our studies contrast how Msh2-Msh3 and Msh2-Msh6 navigate on a crowded genome and

160 and purification of Saccharomyces cerevisiae Msh2-Msh3 and performed a comparative study of Msh2-Msh3

161 udies in knockout mice provide evidence that MSH2-MSH3 and the BER machinery promote trinucleotide re

162 egions but not the mispair binding domain of Msh2-Msh3 are responsible for the extremely rapid dissoc

163 In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions an

164 airs and small insertion/deletion loops, and Msh2-Msh3 binds larger insertion/deletion loops.

165 Our results show that the MSH2-MSH3 complex is important for the suppression of la

166 n Msh2-Msh6/Msh3 chimeric protein and mutant Msh2-Msh3 complexes showed that the nucleotide binding d

167 Msh2-Msh3 formed sliding clamps and recruited Mlh1-Pms1

168 t, msh2Delta1 mutants show strong defects in Msh2-Msh3 functions.

169 ce, of the mismatch repair protein MutSbeta (Msh2-Msh3 heterodimer).

170 Msh2-Msh3 hops over nucleosomes and other protein roadbl

171 t amino acid residues predicted to stabilize Msh2-Msh3 interactions with bent, strand-separated mispa

172 Msh2-Msh3 is also required for 3' non-homologous tail re

173 irst molecular crosstalk mechanism, in which MSH2-MSH3 is used as a component of the BER machinery to

174 navigate on a crowded genome and suggest how Msh2-Msh3 locates DNA lesions outside of replication-cou

175 is initiated by either the Msh2-Msh6 or the Msh2-Msh3 mispair recognition heterodimer.

176 Remarkably, MSH2-MSH3 not only stimulates pol beta to copy through t

177 ible for the extremely rapid dissociation of Msh2-Msh3 sliding clamps from DNA relative to that seen

178 Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulat

179 ompared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromo

180 ggesting a modulating role for the MutSbeta (MSH2-MSH3) complex in late-onset tumorigenesis.

181 ' to the mispair, a mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA, and Pol epsilo

182 A mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA, and Pol epsilo

183 irected MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A

184 substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not require nicking of

185 activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), a

186 cule fluorescence imaging to investigate how Msh2-Msh3, a eukaryotic mismatch repair complex, navigat

187 h genetic data on the mispair specificity of Msh2-Msh3- and Msh2-Msh6-dependent mismatch repair in vi

188 f insertion/deletion loops is carried out by Msh2-Msh3-mediated mismatch repair (MMR).

189 eotide binding pocket that are essential for Msh2-Msh3-mediated MMR but are largely dispensable for 3

190 and showed that it is a metal-dependent and Msh2-Msh3-stimulated endonuclease that makes single-stra

191 or nucleotide binding and/or exchange within Msh2-Msh3.

192 MSH2/MSH3 binds, bends, and dissociates from repair-comp

193 y of the Rad1/Rad10 complex, Saw1, Slx4, and Msh2/Msh3 complex at a 3' tailed recombination intermedi

194 ng, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.

195 que DNA junction that traps nucleotide-bound MSH2/MSH3, and inhibits its dissociation from the DNA.

196 eport that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and

197 type, Polzeta(+/-), Polzeta(-/-), Ung(-/-), Msh2(-/-), Msh6(-/-), and Ung(-/-) Msh2(-/-) clones sugg

198 deleterious mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cance

199 in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2.

200 Immunohistochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 protein expression and microsatelli

201 resence of 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in these tumors.

202 dy of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referra

203 ing the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mut

204 Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncatin

205 ed on loss of mismatch repair proteins MLH1, MSH2, MSH6, and/or PMS2.

206 d the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1.

207 ations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant o

208 crosatellite instability, namely MLH1, PMS2, MSH2, MSH6, P53 and PTEN.

209 ons in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patie

210 variants in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM).

211 Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq an

212 It forms the MSH2-MSH6 (MutSalpha) and MSH2-MSH3 (MutSbeta) heterodim

213 ained a nick 3' to the mispair, a mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA,

214 A mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA,

215 dent 3' nick-directed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replicat

216 lh1-Pms1 with substrate DNA, with or without Msh2-Msh6 (or Msh2-Msh3), PCNA, and RFC but did not requ

217 1 endonuclease activation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear ant

218 h the ability to form a ternary complex with Msh2-Msh6 and mismatch DNA.

219 isualized functional fluorescent versions of Msh2-Msh6 and Mlh1-Pms1 in living cells.

220 or the mispair-dependent interaction between Msh2-Msh6 and Mlh1-Pms1.

221 h it has been demonstrated that both UNG and Msh2-Msh6 are important for introduction of S region DSB

222 eins had defects either in trimerization and Msh2-Msh6 binding or in activation of the Mlh1-Pms1 endo

223 In initial steps in MMR, Msh2-Msh6 binds mispairs and small insertion/deletion lo

224 air recognition and Mlh1-Pms1 recruitment by Msh2-Msh6 but not sliding clamp formation.

225 siae, mispairs are primarily detected by the Msh2-Msh6 complex and corrected following recruitment of

226 We found that the Msh2-Msh6 complex is an S phase component of replication

227 ven conformational change and resulted in an Msh2-Msh6 complex that bound mispaired bases but could n

228 mispaired bases was increased; in contrast, Msh2-Msh6 foci were unaffected.

229 med nuclear foci that, although dependent on Msh2-Msh6 for formation, rarely colocalized with Msh2-Ms

230 rformed a comparative study of Msh2-Msh3 and Msh2-Msh6 for mispair binding, sliding clamp formation,

231 nd CC, AA, and possibly GG mispairs, whereas Msh2-Msh6 formed mispair-dependent sliding clamps and re

232 Supporting this hypothesis, Msh2-Msh6 have been shown to contribute to DSB formation

233 anced by an msh6 mutation that disrupted the Msh2-Msh6 interaction with PCNA.

234 xo1-independent MMR pathway and suggest that Msh2-Msh6 localizes PCNA to repair sites after mispair r

235 cyclins to restrict the availability of the Msh2-Msh6 mismatch recognition complex to either S phase

236 ATP binding causes the mispair-bound Msh2-Msh6 mismatch recognition complex to slide along th

237 recognition protein could substitute for the Msh2-Msh6 mispair recognition protein and showed a diffe

238 Our studies contrast how Msh2-Msh3 and Msh2-Msh6 navigate on a crowded genome and suggest how M

239 In the other, Msh2-Msh6 or Msh2-Msh3 activate the MutL homolog 1 (Mlh1

240 A mismatch repair is initiated by either the Msh2-Msh6 or the Msh2-Msh3 mispair recognition heterodim

241 es suggest that pol zeta may function in the MSH2-MSH6 pathway.

242 The heterodimeric human MSH2-MSH6 protein initiates DNA mismatch repair (MMR) by

243 nts reveal msh2Delta1-specific phenotypes in Msh2-Msh6 repair, with significant effects on mutation r

244 -Msh6 for formation, rarely colocalized with Msh2-Msh6 replication-associated foci.

245 In contrast, Msh2-Msh6 slides without hopping and is largely blocked

246 ly with UNG and the mismatch repair proteins Msh2-Msh6 to Ig Smu and Sgamma3 regions, and this depend

247 air-binding domain (MBD) licences a chimeric Msh2-Msh6(3MBD) to bypass nucleosomes.

248 ation of recombinant native human MutSalpha (MSH2-MSH6) and MutLalpha (MLH1-PMS2) proteins, and in vi

249 ng clamps from DNA relative to that seen for Msh2-Msh6, and that amino acid residues predicted to sta

250 ependent pathways for mispair recognition by Msh2-Msh6, which direct formation of superstoichiometric

251 on the mispair specificity of Msh2-Msh3- and Msh2-Msh6-dependent mismatch repair in vivo.

252 main I of Msh2, does not dramatically affect Msh2-Msh6-dependent repair.

253 Analysis of an Msh2-Msh6/Msh3 chimeric protein and mutant Msh2-Msh3 com

254 s that ATP induces conformational changes in Msh2-Msh6; however, the nature of these conformational c

255 mans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo.

256 cosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate cla

257 ding 10 MSH6 mutation carriers (0.45%) and 4 MSH2 mutation carriers (0.18%).

258 MSH2 mutation carriers had a considerably higher risk of

259 Among MSH2 mutation carriers, mutations in MSH2 (the most prev

260 2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 x 10(-5)).

261 2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing cr

262 ispair binding by either the MutS homolog 2 (Msh2)-MutS homolog 6 (Msh6) or the Msh2-MutS homolog 3 (

263 A mixture of MutS homolog 2 (Msh2)-MutS homolog 6, Exonuclease 1, replication protein

264 omolog 2 (Msh2)-MutS homolog 6 (Msh6) or the Msh2-MutS homolog 3 (Msh3) stimulates 5' to 3' excision

265 The Msh2-MutS homolog 3 mispair recognition protein could su

266 t cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCA

267 8 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308).

268 lyposis colorectal cancer map to domain I of Msh2; none have been found in MSH3.

269 Msh2-null mice were also impaired in locomotive activity

270 he myelinated corpus callosum projections of Msh2-null mice were smaller than wild-type mice, whereas

271 MSH2, on the other hand, which is generally thought to p

272 mutations in or near the ATP binding site of MSH2 or ATP hydrolysis catalytic site of MSH6 develop ca

273 Human or mouse cells lacking MSH2 or MLH1 display increased sensitivity and radial fo

274 rmline mutation in 1 allele of the MMR genes MSH2 or MLH1.

275 at later ages than carriers of mutations in MSH2 or MLH1.

276 show that simultaneous deficiency of UNG and MSH2 or MSH2 alone causes genomic instability and a shor

277 We now show that shRNA knockdown of either MSH2 or MSH3 slowed GAA.TTC expansion in our system.

278 Mutations are frequently complex MSH2 or MSH6 structural rearrangements rather than MLH1

279 tations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1

280 atellite instability phenotype compared with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tum

281 Overall, our results suggest a novel USP10-MSH2 pathway regulating DNA damage response and DNA mism

282 MSH2 preferentially binds a cisplatin interstrand cross-

283 y are opposed by the protective influence of MSH2, producing a net protective effect that promotes im

284 tone H3 acetylation, and hypermethylation of MSH2 promoter were also observed in Caki-1 cells adapted

285 contains a 3' protruding nonhomologous tail, Msh2 promotes the rejection of mismatched substrates.

286 es in human leukemia cells recapitulated the MSH2 protein deficiency by enhancing MSH2 degradation, l

287 degradation result in undetectable levels of MSH2 protein in leukemia cells, DNA mismatch repair defi

288 Previous studies showed that the level of MSH2 protein is modulated by the ubiquitin-proteasome pa

289 phoblastic leukemia have low or undetectable MSH2 protein levels, despite abundant wild-type MSH2 mRN

290 ismatch repair was low levels of the variant Msh2 proteins.

291 the deubiquitinating enzymes, which regulate MSH2 remain unknown.

292 In addition to its DNA repair function, MSH2 serves as a sensor for DNA base analogs-provoked DN

293 Among MSH2 mutation carriers, mutations in MSH2 (the most prevalent mutations overall) were most co

294 zolomide-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient re

295 ajor mechanism for increased turnover of the Msh2 variants and identified the primary ubiquitin ligas

296 polymorphisms and was used to investigate 59 Msh2 VUS.

297 the miR-21 tumor-related targets, including MSH2, was observed in Ras-transformed keratinocytes.

298 nograft model of human GBM, small changes in MSH2 were sufficient to suppress temozolomide-induced tu

299 MutSalpha proteins MSH2(G674A)-MSH6(wt) and MSH2(wt)-MSH6(T1219D) are profiled in a variety of funct

300 MSH2(wt)-MSH6(T1219D) fails to couple nucleotide binding