ライフサイエンスコーパス: MSH3

1 the requirements for mispair interaction by Msh3.

2 r in that Top1 removal does not require Msh2-Msh3.

3 ditional DNA mismatch repair genes, MSH6 and MSH3.

4 mutations in the Apc gene were suppressed by Msh3.

5 lso on the mismatch repair proteins Msh2 and Msh3.

6 d by the msh2 mutation and about 100-fold by msh3.

7 nhances the mismatch binding ability of MSH2-MSH3.

8 ns in FEN1 (the human homolog of RTH) and in MSH3.

9 bination of either MSH2 and MSH6 or MSH2 and MSH3.

10 mismatch repair genes MSH2, MLH1, PMS1, and MSH3.

11 rmline mutations in the mismatch-repair gene MSH3.

12 nd encodes an aminoacid change (Pro67Ala) in MSH3.

13 cleotide binding and/or exchange within Msh2-Msh3.

14 pect to the position of the bound ATP within Msh3.

15 to domain I of Msh2; none have been found in MSH3.

16 fluorescence imaging to investigate how Msh2-Msh3, a eukaryotic mismatch repair complex, navigates on

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

18 Mispair binding analysis with purified Msh2-Msh3 and DNA substrates derived from CAN1 sequences foun

19 titive DNA sequences is coincident with MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, sugge

20 ond complex involves MLH3 together with MSH2-MSH3 and localizes to repetitive sequences at centromere

21 us for mutations at the Msh3, Msh2, and both Msh3 and Msh2 loci (2).

22 DSB-induced gene conversion differently from msh3 and msh2, which are also defective in removing nonh

23 Msh2-Msh3 and Msh2-Msh6 are two partially redundant mispair-r

24 These data indicate that eukaryotic Msh2-Msh3 and Msh2-Msh6 complexes are targets for inhibition

25 h3 and performed a comparative study of Msh2-Msh3 and Msh2-Msh6 for mispair binding, sliding clamp fo

26 n of function phenotype with respect to MSH2-MSH3 and MSH2-MSH6 functions.

27 epair with either MSH3 or MSH6, and the MSH2-MSH3 and MSH2-MSH6 heterodimers have a role in the recog

28 humans have indicated a requirement for MSH2-MSH3 and MSH2-MSH6 heterodimers in mismatch recognition.

29 In eukaryotes the MSH2-MSH3 and MSH2-MSH6 heterodimers initiate mismatch repair

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

31 the ATPase domain is conserved between Msh2-Msh3 and Msh2-Msh6.

32 c protein complexes of MutS homologues, MSH2-MSH3 and MSH2-MSH6.

33 with mispair-binding protein complexes, MSH2.MSH3 and MSH2.MSH6, and that PCNA enhances MSH2.MSH6 mis

34 ult in genomic instability and, as in yeast, MSH3 and MSH6 are partially redundant for mismatch repai

35 mmon in HNPCC families, whereas mutations in MSH3 and MSH6 are rare.

36 ir in conjunction with MSH3 or MSH6 and that MSH3 and MSH6 constitute alternate pathways of MSH2-depe

37 We have conducted a comparative analysis of Msh3 and Msh6 deficiency in mouse intestinal tumorigenes

38 The redundancy of MSH3 and MSH6 explains the greater prevalence of hmsh2 m

39 t cells harboring null mutations in both the MSH3 and MSH6 genes exhibit microsatellite instability a

40 een observed in the TGFbetaRII, BAX, IGFIIR, MSH3 and MSH6 genes in colon and other cancers.

41 utational spectra and clarified the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis

42 Thus, MSH3 and MSH6 interactions with PCNA may facilitate earl

43 ns similarly, analyses of reversion rates in msh3 and msh6 mutants revealed distinct specificities of

44 MSH3 and MSH6 peptides containing these motifs bound PCN

45 interaction between the MSH2 protein and the MSH3 and MSH6 proteins.

46 The mismatch repair components MSH2, MSH3 and MSH6 were highly expressed in iPSCs compared wi

47 MutS that function in these processes, Msh2, Msh3 and Msh6, are involved in the mismatch repair of mu

48 Here we report that MSH3 and MSH6, but not MSH2, contain N-terminal sequence

49 MSH2 and preventing it from interacting with MSH3 and MSH6.

50 urification of Saccharomyces cerevisiae Msh2-Msh3 and performed a comparative study of Msh2-Msh3 and

51 Promoter methylation in MLH1, MLH3, MSH3 and PMS2 was also found to be significantly associa

52 ered mechanism of TGR in the absence of Msh2:Msh3 and Rad1 reveals a separate role for these proteins

53 possessed the mispair-binding specificity of Msh3 and revealed that communication between the MBD and

54 rovide a single, isogenic system to add back Msh3 and test key biochemical features of MutSbeta on ex

55 in knockout mice provide evidence that MSH2-MSH3 and the BER machinery promote trinucleotide repeat

56 clones, whereas mutations were dispersed in Msh3(-/-) and wild-type clones.

57 known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as ca

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

59 In this study the role of MSH2, MSH3, and MSH6 in mismatch repair has been examined by m

60 h1 segregation data with that of pms1, msh2, msh3, and msh6 mutants show that the ability to promote

61 s containing different combinations of msh2, msh3, and msh6 mutations and by studying the physical in

62 our data suggest that MutS homologues Msh2, Msh3, and Msh6 play overlapping and distinct roles durin

63 The mismatch repair enzymes MSH2, MSH3, and MSH6, implicated in repeat instability in othe

64 ree genes involved in mismatch repair--MSH2, MSH3, and MSH6--and one in nucleotide excision repair, R

65 es homologous to Escherichia coli mutS-MSH2, MSH3, and MSH6-function in MMR by recognizing mispaired

66 ously identified human MutS homologues MSH2, MSH3, and MSH6-genes that are involved in the pathogenes

67 ly similar to eukaryotic MutS homologs-MSH2, MSH3, and MSH6.

68 tudies of the Saccharomyces cerevisiae MSH2, MSH3, and MSH6.

69 rt substrates requires the products of MSH2, MSH3, and RAD1 and that these proteins have functions in

70 1 interacts physically with Rad1/Rad10, Msh2/Msh3, and Rad52 proteins, and cells lacking SLX4 or SAW1

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

72 Therefore, we sequenced V and S regions from Msh3- and Msh6-deficient mice and compared mutations to

73 When the Msh3-/- and Msh6-/- mutations are combined, the tumor pr

74 cific DNA binding activity while domain I of MSH3 appeared important for mismatch binding specificity

75 tion of small insertion/deletion mispairs by Msh3 appears to require a greater degree of interactions

76 s but not the mispair binding domain of Msh2-Msh3 are responsible for the extremely rapid dissociatio

77 MutSalpha (MSH2/MSH6) and MutSbeta (MSH2/MSH3) are eukaryotic mismatch recognition proteins that

78 amilies, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-polyposis color

79 icantly from lymphoma to sarcoma, indicating MSH3 as a potent modulator of p53-driven tumorigenesis.

80 methylation was seen in MLH1, PMS2, MLH3 and MSH3 as well as significant heterogeneity for both MSI a

81 odimers AtMSH2*MSH6 (AtMutSalpha) and AtMSH2*MSH3 (AtMutSbeta) were previously found to bind the same

82 expansions as Msh3-/- cells, indicating that Msh3 ATPase function is critical for expansions.

83 he abundance of MutSbeta and rely heavily on Msh3 ATPase function.

84 homogeneity, and examined its effect on MSH2-MSH3 binding to DNA mismatches.

85 Therefore, MSH2-MSH3 binding to its substrates creates a unique nucleopr

86 t that the mismatch repair (MMR) factor MSH2-MSH3 binds and stabilizes branched recombination interme

87 In both pathways, Msh2-Msh3 binds double-strand/single-strand junctions and ini

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

89 MSH2/MSH3 binds, bends, and dissociates from repair-competent

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

91 annealing also requires Rad1/Rad10 and Msh2/Msh3, but reveals a difference in their roles.

92 tations in the mismatch repair genes MSH2 or MSH3, but unaffected by a mutation in the nucleotide exc

93 Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of

94 utations in several genes, including RTH and MSH3, cause microsatellite instability.

95 Msh3-/- cells are severely defective for CTG*CAG repeat

96 Msh3-/- cells provide a single, isogenic system to add b

97 mal levels was as defective in expansions as Msh3-/- cells, indicating that Msh3 ATPase function is c

98 Analysis of an Msh2-Msh6/Msh3 chimeric protein and mutant Msh2-Msh3 complexes sho

99 nation of Cr-treated cells revealed MSH6 and MSH3 chromatin foci that originated in late S phase and

100 the Rad1/Rad10 complex, Saw1, Slx4, and Msh2/Msh3 complex at a 3' tailed recombination intermediate.

101 Our results show that the MSH2-MSH3 complex is important for the suppression of late-on

102 the MSH2-MSH6 heterodimer, but not the MSH2-MSH3 complex, is responsible for modulating Ig hypermuta

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

104 2-Msh6/Msh3 chimeric protein and mutant Msh2-Msh3 complexes showed that the nucleotide binding domain

105 ons and CSR was greatly reduced, making Msh2/Msh3 contributions unlikely.

106 These results suggest that MSH3 cooperates with MSH6 in tumor suppression.

107 es to arsenate-resistant proteins, including MSH3, COX10, GCSH, PPOX, and MTHFD1, were also identifie

108 In mice, ablation of Msh2 or Msh6, but not Msh3, decreases levels of switch recombination and dimin

109 gether, our results support the concept that MSH3 deficiency causes EMAST or EMAST with low levels of

110 ely, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of plati

111 However, when Msh3 deficiency is combined with Msh6 deficiency (Msh3(-

112 this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and

113 sion in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and o

114 e prediction and treatments for cancers with MSH3 deficiency.

115 In contrast, Msh3-deficient Apc1638N mice showed no difference in sur

116 Msh3-deficient cells displayed a modest (16-fold) elevat

117 rt that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAST phenotype and low

118 Furthermore, MSH3-deficient cells maintained higher levels of phospho

119 3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(

120 ine kinase 1 (HSV-tk1) gene was unchanged in Msh3-deficient ES cell lines but markedly elevated in Ms

121 reduced heavy chain class switching, whereas Msh3-deficient mice had normal antibody responses.

122 f a linear DNA fragment into the genome, the msh3 delta mutation has an effect on recombination simil

123 at cadmium inhibits both Msh2-Msh6- and Msh2-Msh3-dependent human MMR activity in vitro.

124 specific insertion/deletion mispairs by the MSH3-dependent mismatch repair pathway uses a heterodime

125 nferred a defect in both MSH2-MSH6- and MSH2-MSH3-dependent mismatch repair pathways.

126 egulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that

127 mutation alleles of Saccharomyces cerevisiae msh3 designed to disrupt mispair recognition fell into t

128 initiation became suppressed from within the Msh3, DHFR, and 2BE2121 transcription units.

129 (-10)) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2.

130 The mismatch repair mutations pms1, msh2 and msh3 did not affect 31- and 61-bp deletions in the pol3-

131 MSH2-MSH3 directs the repair of insertion/deletion loops of u

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

133 hereas the hom3-10 reversion rate in an mlh3 msh3 double mutant was the same as in the respective sin

134 tide repeat, whereas Msh2-deficient and Msh2 Msh3 double-mutant cells displayed markedly increased le

135 to be mutated in vivo demonstrated that Msh2-Msh3 exhibited robust binding to specific base-base misp

136 the mispair, a mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA, and Pol epsilon was

137 A mixture of Msh2-Msh6 (or Msh2-Msh3), Exo1, RPA, RFC-Delta1N, PCNA, and Pol epsilon was

138 ed MMR reaction requiring Msh2-Msh6 (or Msh2-Msh3), exonuclease 1 (Exo1), replication protein A (RPA)

139 An ATPase-defective Msh3 expressed at normal levels was as defective in expa

140 sing isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a T

141 etion of SGS1, suggesting that Rad1 and Msh2:Msh3 facilitate TGR while Sgs1 opposes it.

142 The chromosomal double mutant msh3-FF>AA msh6-FF>AA eliminating the conserved FF resid

143 Formation of MSH3 foci was MSH6 and MLH1 dependent, whereas MSH6 foci

144 Here, we find that MSH2 and MSH3 form another stable heterodimer, and we purify this

145 Msh2-Msh3 formed sliding clamps and recruited Mlh1-Pms1 on +1

146 show that the mismatch repair genes MSH2 and MSH3 function in mitotic recombination.

147 Epistasis analyses indicate that MSH2 and MSH3 function in the RAD1-RAD10 recombination pathway, a

148 h2Delta1 mutants show strong defects in Msh2-Msh3 functions.

149 Together the data suggest that the MSH3 gene encodes a product that functions in repair of

150 The MSH3 gene is one of the DNA mismatch repair (MMR) genes

151 role in mismatch repair (MMR), the MSH2 and MSH3 gene products are required to remove 3' nonhomologo

152 Introducing chromosome 5, encoding the MSH3 gene, into the mutant cell line increased the stabi

153 We show that both MSH6 and MSH3 genes are essential for normal genomic stability.

154 spans the dihydrofolate reductase (DHFR) and MSH3 genes.

155 tutions in the PCNA binding motif of Msh6 or Msh3 had elevated mutation rates, indicating that these

156 Accordingly, MSH3 has been suggested as a therapeutic target for CAG.

157 We show that MSH2-MSH3 has low affinity for a G/T mismatch but binds to in

158 en the annealing partners are 1,170 bp, Msh2/Msh3 have little effect, while Rad1/Rad10 are still requ

159 ecific N-terminal regions (NTRs) of Msh6 and Msh3 have not been characterized other than by demonstra

160 e a previously unidentified role of the Msh2-Msh3 heterodimer in the recognition of base-base mispair

161 The Msh2-Msh3 heterodimer recognizes various DNA mispairs, includ

162 f the mismatch repair protein MutSbeta (Msh2-Msh3 heterodimer).

163 n of insertion/deletion mispairs by the Msh2-Msh3 heterodimer.

164 A human MSH2-human MSH3 (hMSH2.hMSH3) complex of approximately 1:1 stoichio

165 Msh2-Msh3 hops over nucleosomes and other protein roadblocks,

166 to the mismatch binding specificity of MSH2-MSH3 in genetic and biochemical assays.

167 However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing

168 ining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effe

169 To better study the role of MSH3 in tumor progression, we crossed Msh3(-/-) mice ont

170 the DNA mismatch repair genes pms1, msh2 and msh3, indicating that this effect does not require a fun

171 Ectopic expression of MSH2 and MSH3 induced GAA.TTC repeat expansion in the native FXN

172 no acid residues predicted to stabilize Msh2-Msh3 interactions with bent, strand-separated mispair-co

173 Msh2-Msh3 is also required for 3' non-homologous tail removal

174 anneal are 205 bp, the requirement for Msh2/Msh3 is as great as for Rad1/Rad10; but when the anneali

175 ue (Msh)6 (in conjunction with Msh2) but not Msh3 is involved in generating A/T base substitutions in

176 The absence or reduction of MSH3 is not strongly associated with cancer predispositi

177 clude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account

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

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

180 Here, we report that MutS homologue 3 (MSH3) knockdown or MSH3-deficient cells exhibit the EMAS

181 Because Msh3 lacks these conserved residues, we constructed a se

182 oss of the DNA mismatch repair (MMR) protein MSH3 leads to the development of a variety of tumors in

183 -null HCT116 cells activated an alternative, MSH3-like activity that restored dinucleotide repeat sta

184 an Msh2 MBD deletion mutant, indicating that Msh3-like behaviors beyond mispair specificity are not f

185 ate on a crowded genome and suggest how Msh2-Msh3 locates DNA lesions outside of replication-coupled

186 Our results suggest that MSH3 may also serve as a therapeutic target to slow the

187 ing of the two classes of mutations onto the Msh3 MBD model appears to distinguish mispair recognitio

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

189 se strains were completely defective in MSH2-MSH3-mediated MMR and recombination functions.

190 e binding pocket that are essential for Msh2-Msh3-mediated MMR but are largely dispensable for 3' NHT

191 MutSbeta (MSH2-MSH3) mediates repair of insertion-deletion heterologies

192 )(/)(-) mice have a decrease in CSR, whereas Msh3(-)(/)(-) mice do not.

193 Although none of these changes were seen in Msh3(-)(/)(-) mice, they had a higher percentage of larg

194 In contrast, Msh3(-)/- mice show no differences from their littermate

195 ole of MSH3 in tumor progression, we crossed Msh3(-/-) mice onto a tumor predisposing p53-deficient b

196 Cells from Msh3-/- mice are defective in repair of insertion/ delet

197 Msh3-/- mice develop tumors at a late age.

198 th MSH2-MSH3 and is decreased in Msh2-/- and Msh3-/- mice, suggesting a novel role for the MMR family

199 t interfere with both the Msh2-Msh6 and Msh2-Msh3 mismatch recognition complexes.

200 endonucleases and also associates with MSH2/MSH3 mismatch repair complex, telomere binding complex T

201 id BY4741, has an additional mutation in the MSH3 mismatch repair gene.

202 mbination was not altered by pms1, msh2, and msh3 mismatch repair mutations.

203 MSH2 that act as if they inactivate the Msh2-Msh3 mispair recognition complex thus causing weak MMR d

204 nitiated by either the Msh2-Msh6 or the Msh2-Msh3 mispair recognition heterodimer.

205 ndent of the mismatch correction genes MSH2, MSH3, MLH1, and PMS1, as judged by activity in mutant ex

206 ns in the yeast mismatch repair genes, MSH2, MSH3, MLH1, and PMS1.

207 Interestingly, Msh3(-/-) mouse embryonic fibroblasts displayed increase

208 but markedly elevated in Msh2-deficient and Msh3 Msh2 double-mutant cells.

209 ) cell lines homozygous for mutations at the Msh3, Msh2, and both Msh3 and Msh2 loci (2).

210 tivity is observed in extracts from an msh2- msh3- msh4- strain.

211 MSH2 and RAD10 were found to interact in msh3 msh6 and mlh1 pms1 double mutants, suggesting a dir

212 ve mismatch repair system (msh2, msh3, msh6, msh3 msh6, pms1, and mih1 mutants).

213 In Msh6(-)/- and Msh3(-)/-/Msh6(-)/- mice, base substitutions are prefere

214 tinal tumors from both Msh6(-/-)Apc1638N and Msh3(-/-)Msh6(-/-)Apc1638N mice contained truncation mut

215 However, in Msh3(-/-)Msh6(-/-)Apc1638N tumors, we observed a mixture

216 deficiency is combined with Msh6 deficiency (Msh3(-/-)Msh6(-/-)Apc1638N), the survival rate of the mi

217 sis by generating Apc1638N mice deficient in Msh3, Msh6 or both.

218 tor mutations were identified in MLH1, MSH2, MSH3, MSH6, and EXO1.

219 n Saccharomyces cerevisiae, the MMR proteins Msh3, Msh6, and Mlh1 interact with proliferating cell nu

220 epeats in the TGFbetaIIR, IGFIIR, BAX, E2F4, MSH3, MSH6, BRCA1, and BRCA2 genes were generally rare.

221 inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Sacchar

222 ectly with several MMR components, including MSH3, MSH6, MLH1, and EXO1.

223 ostreplicative mismatch repair system (msh2, msh3, msh6, msh3 msh6, pms1, and mih1 mutants).

224 air changes from GC to CG and from AT to TA; msh3 mutants also accumulated homology-mediated duplicat

225 Saccharomyces cerevisiae msh3 mutants did not show an increase in the rate of bas

226 spectrum of mlh3 mutants paralleled that of msh3 mutants, suggesting that the Mlh1-Mlh3 heterodimer

227 The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and

228 The msh2 and msh3 mutations destabilized microsatellites with repeat

229 sent study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditar

230 The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent

231 Our data suggest that MSH3 mutations represent an additional recessive subtype

232 e initial recognition of Cr-DNA damage, MSH2-MSH3 (MutSbeta) complex was essential for the induction

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

234 the tissues exhibiting EMAST contained more MSH3-negative cells (average, 31.5%) than did the tissue

235 Although non-MSI-H CRC tissues contained MSH3-negative tumor cells ranging from 2% to 50% of the

236 Remarkably, MSH2-MSH3 not only stimulates pol beta to copy through the re

237 sidues within the FLY motif of the predicted Msh3 nucleotide binding pocket that are essential for Ms

238 Interestingly, chromosome 3 transfer into MSH3-null HCT116 cells activated an alternative, MSH3-li

239 nd governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.

240 MutS homologues specific to either MMR (MSH2-MSH3 or MSH2-MSH6) or crossing over (MSH4-MSH5).

241 tions in mismatch repair in conjunction with MSH3 or MSH6 and that MSH3 and MSH6 constitute alternate

242 Interestingly, although mutations in either MSH3 or MSH6 do not cause the extreme microsatellite ins

243 ve suggested that MSH2 functions with either MSH3 or MSH6 in mismatch repair, and, in the absence of

244 When human MSH3 or MSH6 peptides containing the PCNA binding motif

245 SH2 functions in mismatch repair with either MSH3 or MSH6, and the MSH2-MSH3 and MSH2-MSH6 heterodime

246 is always found as a heterodimer with either Msh3 or Msh6, so it is important to know which one is in

247 d heterodimers of MSH2 complexed with either MSH3 or MSH6.

248 ase Exo1, and mismatch repair mutants (msh2, msh3, or msh6).

249 isruptions of the mismatch repair gene MSH2, MSH3, or PMS1 or the recombination gene RAD52 showed lit

250 s severely inhibited in the absence of MSH2, MSH3, or RAD1 and is relatively insensitive to the prese

251 parent absence of a Saccharomyces cerevisiae MSH3 ortholog in the C. elegans genome, suggests that C.

252 Msh3 overexpression led to high expansion activity and e

253 ere associated with progression in TRACK-HD (MSH3 p=2.94 x 10(-8)DHFR p=8.37 x 10(-7) MTRNR2L2 p=2.15

254 10(-9)) and to a lesser extent in REGISTRY (MSH3 p=9.36 x 10(-4)DHFR p=8.45 x 10(-4)MTRNR2L2 p=1.20

255 Survival of Msh3/p53 mice was not reduced compared with p53 single m

256 Msh3/p53 tumors showed increased loss of heterozygosity,

257 by residues ((L/I)SRFF) embedded within the MSH3 PCNA-binding motif.

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

259 with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double str

260 mutations were obtained in MLH1, PMS1, MSH2, MSH3, POL30 (PCNA), POL32, and RNR1, whereas starting wi

261 Expression of two Msh3 polymorphic variants at normal levels showed no det

262 ter oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an imp

263 vation reaction requiring Msh2-Msh6 (or Msh2-Msh3), proliferating cell nuclear antigen (PCNA), and re

264 gesting these polymorphisms primarily affect Msh3 protein stability, not activity.

265 The possible roles of Msh2, Msh3, Rad1, and Rad10 proteins in genetic recombination

266 A msh3 rad59 double mutant was more severely defective in

267 We suggest Msh2 and Msh3 recognize not only heteroduplex loops and mismatche

268 c MutS homolog complexes, Msh2-Msh6 and Msh2-Msh3, recognize mismatched bases in DNA during mismatch

269 Knockout of Msh3 reduces somatic expansion in Huntington's disease m

270 all insertion/deletion mismatches while MSH2-MSH3 repairs larger insertion/deletion mismatches.

271 tes of frameshift mutations; inactivation of MSH3 results in low rates of frameshift mutations.

272 that in the absence of MSH2 or MSH6, but not MSH3, reversion rates of some mutations are increased by

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

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

275 Remarkably, the Msh3-specific mispair-binding domain (MBD) licences a ch

276 cal footprinting analyses indicate that MSH2-MSH3 specifically binds at the double-strand/single-stra

277 mobility shift assay that S. cerevisiae MSH2-MSH3 specifically binds branched DNA substrates containi

278 endent, whereas MSH6 foci were unaffected by MSH3 status.

279 showed that it is a metal-dependent and Msh2-Msh3-stimulated endonuclease that makes single-strand br

280 homolog 6 (Msh6) or the Msh2-MutS homolog 3 (Msh3) stimulates 5' to 3' excision by exonuclease 1 (Exo

281 osatellite alterations in the pms1, msh2 and msh3 strains were additions or deletions of single GT re

282 Further, they demonstrate that MSH2-MSH3 suppresses chromosomal instability and modulates th

283 ed with Msh2/p53 tumors, revealing that MSH2-MSH3 suppresses tumorigenesis by maintaining chromosomal

284 ubject to mismatch repair by the PMS1, MSH2, MSH3 system and that in cannot act on loops > or = 31 ba

285 vivo analysis of well-conserved residues in Msh3 that are hypothesized to be required for MMR and/or

286 Here, we show that MSH3, the MSH2-binding partner in the MutSbeta complex,

287 It interacts with MSH6 or MSH3 to form the MutSalpha or MutSbeta complex, respecti

288 matches and suggest that the binding of MSH2-MSH3 to mismatch DNA involves protein-DNA contacts that

289 otide insertion/deletion mismatches and with MSH3 to recognize small loop insertion/deletion mismatch

290 MSH3, together with MSH2, forms the MutSbeta heteroduple

291 endonuclease Rad1/Rad10 but also on Msh2 and Msh3, two proteins that are required to correct mismatch

292 eling of the mispair-binding domain (MBD) of Msh3 using the related Msh6 MBD revealed that mismatch r

293 sh6 was replaced by the equivalent domain of Msh3 was functional for mismatch repair.

294 This role of MSH3 was further supported by our findings that MSH3-def

295 Here, human Msh3 was mutated to selectively inactivate MutSbeta.

296 Whereas MSH3 was not involved in any family, a large Amsterdam-p

297 no FEN1 mutations, a frameshift mutation in MSH3 was observed in an endometrial carcinoma and in an

298 In strains deleted of RAD1, MSH2, or MSH3, we find that the frequency of TGR is reduced and t

299 To examine the role of MSH3, we generated a mouse with a null mutation in this

300 MSH2 and MSH3, which encode subunits of Msh2/3, a complex active