ライフサイエンスコーパス: PMS2

1 tch repair proteins MLH1, MSH2, MSH6, and/or PMS2.

2 ast one related gene resembles the 3' end of PMS2.

3 proapoptotic function by cisplatin requires PMS2.

4 l change for Mlh1 was more apparent than for Pms2.

5 ferential conformational changes in Mlh1 and Pms2.

6 e role of Msh2 differs from that of Mlh1 and Pms2.

7 showed more tumor foci with loss of PMS1 and PMS2.

8 n both Apc and the DNA mismatch repair gene, Pms2.

9 repair gene Xpa or the mismatch repair gene Pms2.

10 homologues of the human genes MLH1, PMS1 and PMS2.

11 mismatch repair genes MSH2, MLH1, PMS1, and PMS2.

12 PALB2, PTEN, NBN, RAD51C, RAD51D, MSH6, and PMS2.

13 in mice lacking the DNA mismatch repair gene Pms2.

14 re distinct from those deficient in msh2 and pms2.

15 ndrome-associated genes MLH1, MSH2, MSH6 and PMS2.

16 he endonuclease functions of its MMR partner PMS2.

17 mismatch repair genes: MSH2, MLH1, MSH6, and PMS2.

18 reened for MLH1 methylation and mutations in PMS2.

19 o mismatch repair genes MLH1, MSH2, MSH6 and PMS2.

20 germ line mutations in MLH1, MSH2, MSH6, and PMS2.

21 MSH2; 1, MSH2/monoallelic MUTYH; 2, MSH6; 5, PMS2); 1 patient had the APC c.3920T>A, p.I1307K mutatio

22 In this study we demonstrate that the pms2-1 and pms2-2 alleles arise from missense mutations

23 , 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 ind

24 his study we demonstrate that the pms2-1 and pms2-2 alleles arise from missense mutations in the MLH1

25 One of these alleles, pms2-2, causes the same amino acid substitution in a hig

26 in high-penetrance CRC genes (5, APC; 1, APC/PMS2; 2, biallelic MUTYH; 1, SMAD4); 13 patients had mut

27 Mice deficient in Pms2, a mammalian homolog of bacterial mutL, develop can

28 -) mice, indicating that a single functional Pms2 allele is sufficient to generate normal levels of s

29 It is shown that postmeiotic segregation 2 (PMS2), an MMR protein, is required for cisplatin-induced

30 Here, we describe an interaction between PMS2, an MMR protein, and p73.

31 sequence identity with exons 9 and 11-15 of PMS2 and emanating from a locus close to PMS2 in chromos

32 n model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessme

33 develop intestinal tumors, mice deficient in Pms2 and heterozygous for Min, an allele of Apc, develop

34 ll lines derived from mice deficient for the PMS2 and MLH1 mismatch repair proteins.

35 e base-pair substitutions increased when the Pms2 and Mlh1 null cells were treated with ultraviolet r

36 discussed with regards to the roles for the PMS2 and MLH1 proteins in preventing spontaneous and gen

37 nvolved in mismatch repair and at least two, Pms2 and Mlh1, are essential for meiotic progression in

38 lease and mismatch repair activities of MLH1-PMS2 and MLH1-PMS1, respectively.

39 ation in two MutL types of MMR deficiencies, Pms2 and Mlh1.

40 smatch repair complex MutLalpha, composed of PMS2 and MLH1.

41 Mice with mutations in Mlh1, Pms2 and Msh5 have defects in meiosis suggesting unique

42 smatch repair proteins MSH2, MSH6, MLH1, and PMS2 and occurs by a mechanism that is distinct from tha

43 o cisplatin enhances the association between PMS2 and p73.

44 Germline mutations in the human MSH2, MLH1, PMS2 and PMS1 DNA mismatch repair (MMR) gene homologues

45 ents whose colon tumors stained negative for PMS2 and positive for MLH1 by immunohistochemistry.

46 analysis we show here that human MSH2, MLH1, PMS2 and proliferating cell nuclear antigen (PCNA) can b

47 Mutations within this motif in human PMS2 and Saccharomyces cerevisiae PMS1 disrupted the end

48 ignificant differences were observed between Pms2(+/+) and Pms2(+/-) mice, indicating that a single f

49 in immortalized MMR deficient (Mlh1(-/-) and Pms2(-/-)) and WT MEFs.

50 h mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated

51 Mutated gene (MLH1, MSH2, MSH6, and/or PMS2) and type of mutation (truncating, splicing, or lar

52 s, it causes a reduction of XPA, XPC, hOGG1, PMS2, and MLH1 proteins; this effect, however, can be ne

53 1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspecte

54 analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1 proteins in DU145, LNCaP, p69SV40T, M2182

55 Pms2- and Mlh-1-deficient mice also resemble Msh2-defici

56 We found that both Pms2- and Mlh1-deficient mice can somatically hypermutat

57 T (hMGMT) transgenic mice were mated and the PMS2-/- and PMS2+/+ with or without hMGMT offspring were

58 h1(-/-) mice was 2- to 3-fold higher than in Pms2(-/-) animals.

59 of some residual DNA repair capacity in the Pms2(-/-) animals.

60 ions in T cells and fibroblasts of 129 x C3H Pms2-/-Aprt+/- mice.

61 The MMR proteins MSH2, MSH6, MLH1, and PMS2 are similarly detected in both cell lines.

62 Mice defective in the MMR gene PMS2 are susceptible to spontaneous thymic lymphoma and

63 PMS2-related genes resembling the 5' end of PMS2, at least one related gene resembles the 3' end of

64 n induction of chromosome gaps and breaks in PMS2-, BRCA1-, MSH2-, MLH1-, FHIT-, and TP53-deficient c

65 Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of

66 ers of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-p

67 e-associated tumors showing isolated loss of PMS2 by immunohistochemistry.

68 Amino acid substitution mutations within a PMS2 C-terminal (721)QRLIAP motif attenuate or abolish h

69 stability of the core MMR proteins (MLH1 and PMS2) caused by elevated basal caspase-dependent proteol

70 Contributions by both MLH1/MLH3 and MLH1/PMS2 complexes to mechanisms of mismatch repair-mediated

71 ate IR further showed that nullizygosity for Pms2 confers increased survival on cells in both wild-ty

72 ll colonies analyzed (cell lines HCT 116 and PMS2-/-) contained both the wild-type and mutated PBS, t

73 These results suggest that PMS2 contributes to genome integrity not only through DN

74 eporter gene and an out-of-frame Cre allele (Pms2(cre)) that stochastically becomes functional by a f

75 These data suggest that PMS2 defective lymphomas may arise by the concerted acti

76 of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may re

77 Although Pms2 deficiency clearly increases adenoma formation in t

78 leles is a maternal effect that results from Pms2 deficiency during the early cleavage divisions.

79 utation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nu

80 tion in the early mouse embryo suggests that Pms2 deficiency is a maternal effect, one of a limited n

81 s, the mutator phenotype as a consequence of PMS2 deficiency is tissue-dependent, which may be relate

82 B cells in comparison with Msh2-, Mlh1-, and Pms2-deficient B cells.

83 By contrast, 23% of junctions from Mlh1- and Pms2-deficient cells occurred at unusually long stretche

84 Interestingly, Pms2-deficient males display sterility associated with a

85 r/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can

86 Whereas Pms2-deficient mice do not develop intestinal tumors, mi

87 However, variable genes from PMS2-deficient mice had significantly more adjacent base

88 und in variable genes from XPA-deficient and PMS2-deficient mice, indicating that neither nucleotide

89 ncer susceptibility in Mlh1- versus Mlh3- or Pms2-deficient mice.

90 When expressed in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but n

91 mutable to IR, we compared IR mutagenesis of Pms2-deficient versus wild-type transgenic mice carrying

92 ermutation mechanism and then processed by a PMS2-dependent pathway.

93 tch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2) develop a rare but severe variant of Lynch syndrom

94 es of Msh2 and the MutL homologues, Mlh1 and Pms2, differ.

95 nuclear localization of MutLalpha (the MLH1-PMS2 dimer).

96 Furthermore, Mlh3;Pms2 double-deficient mice have tumor susceptibility, sh

97 between Mlh1(-/-) animals and Mlh1(-/-) and Pms2(-/-) double knockout mice revealed little differenc

98 nuclease active site has been localized to a PMS2 DQHA(X)(2)E(X)(4)E motif.

99 ease that is dependent on the integrity of a PMS2 DQHA(X)2E(X)4E motif.

100 Therefore, the PMS2 endonuclease activity has distinct biological funct

101 the mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM).

102 umor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation f

103 but selectively loses MLH1 and consequently PMS2 expression following inflammation.

104 Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue.

105 Data were collected from 98 PMS2 families ascertained from family cancer clinics tha

106 tic stability, we analyzed F(1) progeny from Pms2(-/-) female mice mated with wild-type males.

107 n detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation ca

108 Mice carrying a mutation in the Pms2 gene are predisposed to lymphomas and other tumors.

109 ent of the MMR complex, yet mutations in the PMS2 gene are rare in the etiology of hereditary nonpoly

110 nch syndrome cases for MSH2, MLH1, MSH6, and PMS2 gene defects.

111 The Pms2 gene has been implicated in hereditary colon cancer

112 e deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3

113 -line mutations in the MLH1, MSH2, MSH6, and PMS2 genes with the use of immunohistochemical staining

114 The clinical consequences of PMS2 germline mutations are poorly understood compared w

115 cted one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mis

116 disrupted allele of the mismatch repair gene Pms2 have a mutator phenotype.

117 We found that MLH1 and PMS2 have functional nuclear localization signals (NLS)

118 Human MutLalpha (MLH1-PMS2 heterodimer) harbors a latent endonuclease that is

119 or mutations that inactivate MutLalpha (MLH1*PMS2 heterodimer).

120 Eukaryotic MutLalpha (mammalian MLH1-PMS2 heterodimer; MLH1-PMS1 in yeast) functions in early

121 c lymphomagenesis was efficiently blocked in PMS2+/+/hMGMT+ mice with rapid repair of O6-meG.

122 The incidence of lymphomas in PMS2-/-/hMGMT+ mice was reduced to 80% (P < 0.01) and me

123 This motif is conserved in eukaryotic PMS2 homologs and in MutL proteins from a number of bact

124 our knowledge this is the first time a human PMS2 homologue has been demonstrated to stimulate a PcrA

125 were repaired by wild-type cells but not by Pms2(-/-) human or murine cells.

126 in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative.

127 of PMS2 and emanating from a locus close to PMS2 in chromosome 7p.

128 studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis.

129 of Msh2, Mlh1, Gtmbp (also known as Msh6) or Pms2 in mice leads to hereditary predisposition to intes

130 reduced, consistent with destabilization of PMS2 in the absence of its heterodimer partner, MLH1.

131 To study the role of Pms2 in the maintenance of in vivo genomic integrity in

132 ences, consistent with an essential role for PMS2 in the repair of replication slippage errors.

133 istent with nonoverlapping roles for p53 and PMS2 in the X-ray response.

134 lease of the MutL homologs PMS1 in yeast and PMS2 in vertebrates.

135 ents), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3).

136 match repair proteins (MLH1, MSH2, MSH6, and PMS2) in these tumors.

137 To determine the effect of Pms2 inactivation on genomic integrity in vivo, hybrid t

138 mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic response to cisplatin

139 e alleles present in small patches of normal Pms2 -/- intestines revealed a general increase in genet

140 d by mismatch repair (MMR) proteins MLH1 and PMS2 is a major component of the MMR complex, yet mutati

141 Pms2 is a MutL homologue that plays a critical role in t

142 Although MLH1/PMS2 is generally thought to have the major MutL activit

143 The human PMS2 is highly polymorphic, with at least 12 known nonsy

144 asked whether nuclear transport of MLH1 and PMS2 is limiting for the nuclear localization of MutLalp

145 f other MMR genes, including Msh2, Msh6, and Pms2, is not altered at the mRNA level.

146 utLalpha, a heterodimer composed of Mlh1 and Pms2, is the major MutL activity in mammalian DNA mismat

147 e DNA methyltransferase (MGMT), heterozygous PMS2 knockout mice and human MGMT (hMGMT) transgenic mic

148 To determine the sensitivity of PMS2 knockout mice to environmental carcinogens and the

149 mismatch-repair genes MLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynch syndrome (here

150 elator desferrioxamine also reduced MLH1 and PMS2 levels, in keeping with low oxygen tension being th

151 ucted that carry targeted disruptions at the Pms2 loci along with a chromosomally integrated mutation

152 This complex is up-regulated in Pms2-/- males, but not females, providing an explanation

153 Functional redundancy among Mlh3, Pms1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice d

154 ismatch repair genes MLH1, MSH2, MLH3, MSH6, PMS2, MGMT and MLH3 via methylation specific multiplex l

155 ferences were observed between Pms2(+/+) and Pms2(+/-) mice, indicating that a single functional Pms2

156 Furthermore, we show that Ung(-/-)Pms2(-/-) mice display a 50% reduction in mutations at A

157 Relevant to this idea, we observed that Pms2(-/-) mice exhibit almost normal levels of Mlh1p, wh

158 U-treated PMS2-/- mice, compared to wildtype PMS2+/+ mice (100 vs 52%; P < 0.001).

159 less than 20% of the DAP(r) mutant clones in Pms2+/+ mice, was predominant in the mutant T cell clone

160 ymphomas was also significantly shortened in PMS2-/- mice (81 vs 102 days, P < 0.01).

161 Fibroblasts of Pms2-/- mice exhibited only a modest increase in the fre

162 thymic lymphomas was observed in MNU-treated PMS2-/- mice, compared to wildtype PMS2+/+ mice (100 vs

163 In contrast to Pms2-/- mice, Pms2EK/EK male mice were fertile, indicati

164 xplanation for the sexual dimorphism seen in Pms2-/- mice.

165 predominant in the mutant T cell clones from Pms2-/- mice.

166 ed to the tissue-specific tumor proneness of Pms2-/- mice.

167 incompletely blocked MNU lymphomagenesis in PMS2-/- mice.

168 number of colon adenomas relative to Min and Pms2+/-;Min mice.

169 Mice null for the Pms2 mismatch repair (MMR) gene exhibit a predisposition

170 D50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated

171 V genes from mice deficient for the MSH2 and PMS2 mismatch repair proteins have frequencies of mutati

172 Additional mismatch repair enzymes (PMS2, MLH1) were targeted, apparently independently.

173 f one of three MMR genes in mammalian cells: Pms2, Mlh1, or Msh2.

174 erize to form three distinct complexes: MLH1/PMS2, MLH1/MLH3, and MLH1/PMS1.

175 wild-type cell lines from related mice, the Pms2-, Mlh1-, or Msh2-nullizygous cell lines were found

176 These results demonstrate that Pms2/Mlh1 and multiple uracil glycosylases act jointly,

177 Paradoxically, the MMR-nicking complex Pms2/Mlh1 is apparently dispensable for A-T mutagenesis.

178 icant promoter methylation was seen in MLH1, PMS2, MLH3 and MSH3 as well as significant heterogeneity

179 ded CAG.CTG repeat in mice deficient for the Pms2 MMR gene.

180 H6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively.

181 ith microsatellite instability, namely MLH1, PMS2, MSH2, MSH6, P53 and PTEN.

182 e hPMS2 cDNA by stable transfection into the PMS2 mutant HEC-1-A cell line.

183 s1 and Pms2 may explain why neither Pms1 nor Pms2 mutant mice develop colon cancer, and why PMS1 and

184 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P

185 We performed PMS2 mutation analysis using long-range polymerase chain

186 represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal can

187 eling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.

188 study was to define the cancer risk faced by PMS2 mutation carriers.

189 described, little is known about disease in PMS2 mutation carriers.

190 linical characteristics of a large series of PMS2 mutation carriers.

191 risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a

192 e defect, mostly involving MSH2 or MLH1; one PMS2 mutation, one MLH1 epimutation, and no MSH6 mutatio

193 Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than fo

194 mice develop colon cancer, and why PMS1 and PMS2 mutations are only rarely found in HNPCC families.

195 sted that contrary to the Knudson principle, PMS2 mutations cause hereditary nonpolyposis colorectal

196 PMS2 mutations contribute significantly to Lynch syndrom

197 formation about the clinical significance of PMS2 mutations is crucial for appropriate counseling.

198 S and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and

199 Germ-line PMS2 mutations were detected in 62% of probands (n = 55

200 MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mut

201 cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mut

202 Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines.

203 As candidates for PMS2 mutations, we selected seven patients whose colon t

204 PMS2 mutations-and perhaps other homozygous mismatch rep

205 on detection, resulting in underdiagnosis of PMS2 mutations.

206 s were observed in Msh2 (MutS homologue) and Pms2 (MutL homologue) MMR-deficient mice.

207 of MutLalpha demonstrated that both Mlh1 and Pms2 N-terminal domains undergo ATP-induced conformation

208 1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22).

209 creased 33-fold and 3.6-20-fold for Mlh1 and Pms2 null cell lines, respectively, when compared with a

210 For the Pms2 null cells this increase resulted from both intrage

211 54% of small events) were predominant in the Pms2 null cells whereas G:C-->A:T transitions (36%) were

212 ith genotypes of either wild type, p53 null, Pms2 null, or double null.

213 xpansion was reduced by approximately 50% in Pms2-null mice.

214 In Pms2 nullizygous animals, the mutation frequency in the

215 SH2 and/or MSH6 expression, isolated loss of PMS2 or loss of MLH1 without MLH1 promoter hypermethylat

216 n patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylati

217 ot change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes, it causes a reduction of XPA, XPC, h

218 rains homozygous for knockouts of either the Pms2 or Mlh1 MMR gene develop cancer but exhibit very di

219 Mice that are deficient in either the Pms2 or Msh2 DNA mismatch repair genes have microsatelli

220 redicted to catalyze ATP hydrolysis of Mlh1, Pms2, or both.

221 c B cells from mice deficient in Msh2, Mlh1, Pms2, or Mlh1 and Pms2 were stimulated in culture with l

222 rtial functional redundancy between MLH3 and PMS2 orthologues for mutation avoidance and show a role

223 mmalian MutL homologs (MLH1, MLH3, PMS1, and PMS2) participate in a variety of events, including post

224 We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

225 Because the absence of MSH2 and PMS2 produced different mutational spectra, we examined

226 However, levels of the PMS2 protein are reduced, consistent with destabilizatio

227 stochemistry (IHC) for MLH1, MSH2, MSH6, and PMS2 protein expression and microsatellite instability (

228 In two additional patients, PMS2 protein from one allele also was abrogated.

229 These mutations abrogated PMS2 protein in germline cells by Western analysis.

230 s was not affected by antibodies against the PMS2 protein, which inhibited long-patch mismatch repair

231 an MutSalpha (MSH2-MSH6) and MutLalpha (MLH1-PMS2) proteins, and in vitro mismatch repair and excisio

232 CA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic

233 d in Pms2-deficient mouse fibroblasts, human PMS2(R20Q) but not PMS2 interfered with the apoptotic re

234 Correspondingly, PMS2 but not PMS2(R20Q) enhanced the cytotoxic effect of cisplatin me

235 Because PMS2(R20Q) lacks proapoptotic activity, this polymorphic

236 We show here that the PMS2(R20Q) variant is defective in activating p73-depend

237 with the idea that dimerization of MLH1 and PMS2 regulates nuclear import by unmasking the NLS.

238 in addition to several previously described PMS2-related genes resembling the 5' end of PMS2, at lea

239 Mutation detection in PMS2 requires haploid DNA.

240 of the four MutL homologues (Mlh1, Mlh3, and Pms2) result in meiotic defects.

241 Cells with either p53 or Pms2 separately disrupted showed reduced levels of apopt

242 ny mutagenic treatment, mice nullizygous for Pms2 showed a 100-fold elevation in mutation frequency i

243 H1 subunit and greatly reduced levels of the PMS2 subunit.

244 erminal endonuclease domain of the MutLalpha PMS2 subunit.

245 s protected at lower ATP concentrations than Pms2, suggesting Mlh1 binds ATP with higher affinity.

246 rupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ov

247 the four MutL homologs, Mlh1, Mlh3, Pms1 and Pms2, three are involved in mismatch repair and at least

248 ations in BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2 to invasive epithelial ovarian cancer (EOC) in the

249 abilization of p73 and the redistribution of PMS2 to the nuclear compartment.

250 utations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers.

251 d the APC c.3920T>A, p.I1307K mutation and a PMS2 variant; 9 patients (18.8%) had double somatic MMR

252 Promoter methylation in MLH1, MLH3, MSH3 and PMS2 was also found to be significantly associated with

253 The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease a

254 or previously described missense variants of PMS2 were detected, but their pathogenicity is undetermi

255 o haploidy, truncating germline mutations of PMS2 were found in two patients (2192delTAACT and deleti

256 the p53 gene or the MutL homologue MMR gene Pms2 were interbred and primary fibroblasts were establi

257 e deficient in Msh2, Mlh1, Pms2, or Mlh1 and Pms2 were stimulated in culture with lipopolysaccharide

258 nt cell clones analyzed (cell lines HeLa and PMS2+/+) were repaired, while 75% were not.

259 repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can

260 loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.

261 l SCAs (p = 2.22 x 10(-4) ) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 x 10(-5) ), all in the same

262 ansgenic mice were mated and the PMS2-/- and PMS2+/+ with or without hMGMT offspring were treated at