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Advances in Brief |
Departments of Cell Biology [W. E., B. K., E. A., E. W.] and Molecular Genetics [W. E., J. H., M. K., M. Lia, E. W., R. K.], Albert Einstein College of Medicine, Bronx, New York 10461; Laboratory of Molecular Genetics, National Institute of Environmental Health Services, Research Triangle Park, North Carolina 27700 [A. U., T. K.]; Strang Cancer Prevention Center, New York, New York 10021 [K. Y., K. F., M. Lip.]; Emory University, Atlanta, Georgia 30322 [G. C.]; Ludwig Institute for Cancer Research, La Jolla, California 92093 [R. D. K.]
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Introduction |
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In human cells, the two protein complexes consisting of MSH2-MSH3 and MSH2-MSH6 appear to be responsible for the recognition of mispaired bases during MMR (3 , 4) . The MSH2-MSH6 complex recognizes single nucleotide and small insertion/deletion mismatches, and the MSH2-MSH3 complex recognizes small insertion/deletion mismatches (3, 4, 5, 6) . Both of these complexes interact with a complex of two MutL-related proteins, MLH1-PMS2, as well as other MMR proteins. These observations suggest that mutations in MSH3 or MSH6 alone or in combination would result in MMR defects and that, therefore, these genes could be involved in cancer predisposition (7) . To test these predictions, we generated mice with mutations in the Msh6 and Msh3 genes and examined their phenotypes.
We have shown that mice carrying an Msh6 mutation have a cancer predisposition phenotype, and it is now established that certain HNPCC cases are the result of germline mutations in this gene (8, 9, 10) . We now show that Msh3-/- mice have defects in the repair of insertion/deletion mismatches, develop tumors late in life, and when combined with Msh6-/- mice, show a phenotype that is indistinguishable from MLH1 or MSH2 deficiency. These results provide an explanation as to why germline mutations in MSH3 have not been detected in HNPCC families. On the basis of these results, we suggest that MSH3 cooperates with MSH6 in tumor suppression.
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Materials and Methods |
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Electroporation of ES Cells.
The targeting vector pMsh3NTK (50 µg) was linearized at the single
NotI site, electroporated into 5.5 x 107 WW6 ES cells, and selected with G418 (150
µg/ml) and ganciclovir (2 µM) as described
previously. Colonies were picked after 9 days, and their DNA was
screened by PCR using forward primer A (5'-CATCTCAGTAGCATCTCACC-3') and
reverse primer B (5'-TGGAAGGATTGGAGCTACGG-3'). The reaction was
performed using the Long Range PCR kit (Boehringer Mannheim) according
to the manufacturer’s specification. Positive ES cell clones were
identified by an 8.8-kb PCR fragment specific for the targeting event.
Five positive cell lines were identified among 232 doubly positive
colonies, and the correct targeting event was shown by BglII
digestion of high molecular weight DNA and Southern blot analysis using
a 1.6 kb KpnI probe directed at the intron 8 region of the
Msh3 gene. A total of five colonies, designated MSH3-48,
-127, -130, -148, and -153, had the correct targeting event.
Generation of Msh3 Mutant Mice.
Two colonies, MSH3-127 and MSH3-130 were injected into C57Bl/6
blastocysts, and the chimeric offspring were tested for germline
transmission. All chimeras tested transmitted the mutation through the
germline. F1 heterozygotes were interbred to
obtain homozygous Msh3 mutant animals. To obtain
Msh3;Msh6 double-mutant animals, Msh3
and Msh6 mutant mice were intercrossed. All of the mice used
for this study were of a mixed genetic background and had an estimated
genetic composition of 60% C57Bl/6, 37.5% 129/Sv, and 2.5% SJL/J.
RNA Analysis.
For Northern blot analysis, Poly(A)+ RNA (5 µg)
from adult liver was separated on 1.0% agarose formaldehyde gels,
transferred to nitrocellulose, and hybridized with an Msh3
probe corresponding to nucleotides 940-2234 (including exons 7–17) of
the coding region and a human Actb (ß-actin) probe. For
RT-PCR analysis, poly(A) RNA (1 µg) was treated with DNase I and
subjected to RT-PCR analysis using the Titan RT-PCR kit (Boehringer
Mannheim) according to the manufacturer’s specification. For the
Dhfr control reaction, primer A (5'-TGGTTCGACCATTGAACTGC-3')
and primer B (5'-CTTGCCAATTCCGGTTGTTC-3'), spanning nucleotides 2–322
of the coding region, were used. Dhfr expression was
indicated by a 321-bp fragment. For the Msh3 reaction,
primer A (5'-AAGAAGGGGAACCTTTCCGT-3') and primer B
(5'-TTGGTGGCTCTTTGGATGAG-3') spanning exons 7 and 8, were used.
Wild-type Msh3 mRNA was indicated by a 322-bp fragment.
Microsatellite Instability Analysis.
DNA was extracted from tumor tissue and subjected to PCR. Four
end-labeled primer pairs were used to amplify sequences containing
dinucleotide repeats (D1 Mit36, D7 Mit91, D10 Mit2, and D14 Mit15; Ref.
12
), and four others were used to amplify sequences
containing mononucleotide repeats [JH 102, JH103, and JH104; primer
sequences were as follows: JH102F, 5'-CATTTCTCTGGGATCGCCTT-3'; JH102R,
5'-CCCGCCTTTGATTCCTTTGT-3'; JH103F,
5'-TTCATCAGTCTTCTGGCTCC-3'; JH103R,
5'-AGTGGTGATAGCAGCTTAGC-3'; JH104F, 5'-AGGTGATTGTAACGGGCATC-3'; and
JH104R, 5'-TATCCTCTCAGTGGTGAGTG-3' (8)
. Primer sequences
for locus U12235 were as follows: P1, 5'-GCTCATCTTCGTTCCCTGTC-3'; and
P3, 5'-CATTCGGTGGAAAGCTCTGA-3' (13)
]. Amplified PCR
products were separated on a denaturing polyacrylamide gel and
autoradiographed for analysis. Instability was expressed as the
percentage of reactions that yielded an abnormal size product.
Cell-free Extracts and MMR Assay.
Procedures for extract and heteroduplex preparation and for
measuring repair activity were as described (14, 15, 16)
.
Analysis of Tumors.
Tumors from sacrificed mice were removed and fixed in 10%
neutral-buffered formalin. The GI tract was opened longitudinally and
examined under a dissecting microscope for the presence of tumors. All
tumors of the GI tract and other tissues were processed for paraffin
embedding, and sections were prepared for staining with H&E.
Statistical analysis of tumor incidence were performed with the
Mann-Whitney test.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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that was transfected into WW6 mouse ES cells. Five of 232
clones examined yielded the 8.3-kb PCR product that was expected from
appropriately modified cells. The targeting events were confirmed by
Southern blot analysis, and cells from two of these colonies,
designated MSH3-127 and MSH3-130, were used to generate mice carrying
the mutation (Fig. 1b)
. We were able to obtain homozygous
Msh3 mutant mice that were viable and reproduced normally.
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. The absence of a wild-type Msh3 transcript
without the neomycin insertion in exon 7 in Msh3-/- mice
was further confirmed by RT-PCR analysis of RNA with a pair of primers
that detect a transcript spanning exons 7 and 8 (Fig. 1d)
.
In this assay, wild-type transcripts were detected in RNA from
heterozygous and wild-type animals but were not found in homozygous
mutant animals, indicating inactivation of the Msh3 gene.
MMR in Msh3-/- Cells.
Microsatellite instability analysis and biochemical MMR assays
performed on MSH2- and MLH1-deficient mice indicated that they were
incapable of repairing single-nucleotide as well as insertion/deletion
mismatches.4
In contrast, cells from Msh6-/- mice were incapable of
repairing single nucleotide mismatches but have a robust repair
activity of insertion/deletion mismatches (8)
. To
ascertain the effect of the Msh3 mutation on repair
activity, cellular extracts from different Msh3 mutant
genotypes were examined for nick-directed MMR. Extracts from wild-type
cells repaired all mismatches tested (Fig. 2
and Refs. 8
, 18
). Extracts of Msh3-/- cells
showed only a partial repair defect. Five different base-base
mismatches and two single-base insertion/deletion mismatches were
repaired, whereas a third single-base insertion/deletion mismatch and
three different substrates containing two extra nucleotides were not
efficiently repaired (Fig. 2)
. To ascertain whether loss of both MSH3
as well as MSH6 would lead to a MMR deficiency that is comparable to
that observed in Msh2-/- or Mlh1-/- cells, we
mated the Msh3 mutant mice with Msh6 mutant mice.
Results from analysis of extracts prepared from
Msh3-/-;Msh6-/- as well as
Msh6-/- cells are shown in Fig. 2
. Compared with the wild
type, the MSH3/MSH6 double-mutant cell extracts failed to correct any
mismatch examined. These results are compatible with the proposed roles
of MSH3 and MSH6 in the DNA MMR process (3, 4, 5, 6, 7
, 19
, 20)
.
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. Msh3-/- mice had a 50% survival time of 22 months, and
their survival was not significantly different from that of the
wild-type control animals (P = 0.0879,
log-rank test). When Msh3-/- mice were compared with
Msh6-/- mice, we noted significant differences. The
Msh6-/- mice had a 50% survival time of 11 months, which
is significantly different from that of Msh3-/- mice
(P < 0.0001, log-rank test; Fig. 3
). These
observations suggest that the presence of MSH6 protein is more critical
to the survival of mice than MSH3. To definitively address the issue of
whether MSH3 has any role in survival, we examined
Msh3-/-;Msh6-/- double-mutant mice. The
survival of the double mutants was significantly lower than the
Msh3-/- or Msh6-/- single mutants (50%
survival age of 6 months: P < 0.0001,
log-rank test). These results show that although MSH3 deficiency alone
does not have a significant effect, it does play a critical role in
survival in combination with an MSH6 deficiency.
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. Msh3+/+ as well as Msh3-/- mice developed
tumors at this old age with a similar incidence. However, the
Msh3-/- mice developed a few GI tumors that were also seen
in Msh2-/-, Mlh1-/-, and
Msh6-/-mice (8
, 18
, 21, 22, 23)
but not in
wild-type mice. Because of the small number of tumors detected in
Msh3-/- mice, it was not possible to definitely conclude
that the absence of MSH3 causes tumor susceptibility.
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, 50% of the double-mutant mice
become moribund or morbid by 5–6 months of age. Among the 16 mice
examined, all had at least one tumor. The tumors were predominantly GI
tumors or non-Hodgkin’s lymphomas (Table 1
and Fig. 4
). This tumor spectrum is very similar to that seen in
Msh6-/- or Mlh1-/- mice examined in our
laboratory or published for Msh2-/- mice (21
, 22)
. When the number of GI tumors per mouse was ascertained,
wild-type mice had no tumors, Msh3-/- mice had
0.13 ± 0.07 tumors, Msh6-/- mice had
0.62 ± 0.24 tumors, and the double-mutant
Msh3-/-;Msh6-/- mice had 2.06 ± 0.45 tumors. The tumors in the double mutants presented at a
much younger age, and the number was significantly greater than those
seen in Msh3-/- (P < 0.001) and
Msh6-/- (P < 0.05) mice.
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Discussion |
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The Msh3 mutant mice contain an insertion into exon 7 of the gene. The insertion introduced multiple stop codons in all three possible reading frames. Because exon 7 is present in all known alternately spliced forms of Msh3 mRNA, no functional mRNAs for Msh3 should be produced in these mice. Consistent with this, no functional MSH3 mRNA was expressed in Msh3-/- cells. Although no direct protein data are available, our data are consistent with the absence of a functional MSH3 protein in Msh3-/- mice. Cell extracts from the Msh3-/- mice had the ability to repair single-nucleotide mismatches and single-nucleotide insertion/deletion mismatches but were defective in repair of larger insertion/deletion mismatches. Earlier results with extracts of Msh6-/- cells showed that these extracts could not repair base-base mismatches but could efficiently repair insertion/deletion mismatches (8) . Extracts of the Msh3-/-;Msh6-/- double-mutant cells were defective in repair of all single-nucleotide mispairs and insertion/deletion mispairs tested. Collectively, these data are consistent with a model [reviewed by Kolodner (7) ] in which base-base mismatches are primarily repaired by the MSH2-MSH6 complex, whereas mismatches involving two or more unpaired nucleotides are repaired by the MSH2-MSH3 complex, and each of the two complexes can function in the repair of single-base insertion/deletion mismatches. The data generally are consistent with many observations on the repair activity of the yeast and human MutS complexes and are consistent with the view that the Msh3 mutation constructed here is a null allele.
Our results show that MSH3 does play a role in suppression of
tumorigenesis. Msh3-/- mice developed a few GI
tumors that were similar to those seen in other MMR-deficient mice. The
development of tumors did not result in increased morbidity, with 50%
of the Msh3-/- mice being alive at 22 months of age
compared with 11 months for Msh6-/- mice and 6–7 months
for Mlh1-/- mice (Fig. 3
and Refs. 23
, 24
).
While this manuscript was under review, another study by de Wind et al. (25) described the results for Msh3 and Msh6 mutant mice on a different genetic background. It is of interest to note that the survival time of these Msh6 mutant mice was shorter compared with the survival of our Msh6 mutant mouse line used in this study and that was reported earlier (8) . The shorter survival seems to be caused by the development of predominantly lymphoid tumors in these animals. Another difference in the tumor spectrum is the presence of gynecological tumors and a relatively low number of intestinal tumors in the Msh6 and Msh3/Msh6 mutant mice. Although an increase in the intestinal tumor number in the double-mutant Msh3/Msh6 animals was observed by these authors, the small number of intestinal tumors in these mouse lines makes the assessment of the roles of Msh3 and Msh6 in intestinal tumorigenesis difficult. These differences between the mouse lines also indicate the influence of genetic modifiers on cancer susceptibility caused by MMR deficiency.
No germline mutations in MSH3 were discovered in HNPCC families. The observations presented in this report are consistent with this observation and may provide an explanation for the lack of germline MSH3 mutations in HNPCC families. If the age of onset of tumors in Msh3-/- mice was translated to human age, it would correspond to a relatively old age. If families with MSH3 mutations exist, the predicted late onset of tumorigenesis and the low tumor incidence would make the identification of such a familial cancer syndrome difficult. The tumor susceptibility profile would likely not satisfy the Amsterdam criteria for HNPCC, at least with regard to age of onset. Why would a Msh3 mutation lead to a much later time of onset of tumorigenesis compared with Msh6 mutant mice? A simple explanation is that the dinucleotide and larger unit repeat sequences that are the major target of mutagenesis in Msh3 mutants are relatively infrequent in coding sequences. This is in contrast to the unique sequences and mononucleotide runs that are the targets of mutagenesis in Msh6 mutants. Thus, defects in MSH3 would produce lower rates of mutations in tumor suppressor genes and proto-oncogenes than the defects caused by a mutation in Msh6. The differences in mutagen sensitivity between Msh3-/- and Msh6-/- cells (25) might also provide an explanation for these differences.
More definitive evidence for the role of MSH3 in tumorigenesis was obtained by combining Msh3 and Msh6 mutations. The combination of Msh3-/- and Msh6-/- mutations resulted in a much greater decrease in survival rate compared with each of the individual mutations and was comparable to that seen in Msh2-/- and Mlh1-/- mutant mice (21, 22, 23, 24) . Tumors from the double-mutant mice also showed a high degree of microsatellite instability, making these double-mutant mice truly analogous to MSH2- or MLH1-deficient mice. The types of tumors seen in these double-mutant mice were very similar to those seen in Msh2-/- and Mlh1-/- mice. Although the Msh3 and Msh6 mutant animals used in this study have a different genetic background than those of the published Msh2 mutant animals, the overall survival rate and the types of GI cancers and lymphomas appear to be the same. These results suggest that MSH3 and MSH6 cooperate in tumor suppression and that inactivation of MSH3 together with MSH6 would cause a susceptibility to intestinal tumors that is indistinguishable from those seen in classic HNPCC patients.
The results from several different laboratories now provide explanations for the roles of all of the mismatch recognition proteins. Because MSH2 is the common subunit of the mismatch recognition complexes, its absence leads to a severe MMR deficiency that affects repair of both single-nucleotide and small insertion/deletion mismatches. The role of MLH1 parallels that of MSH2 in that it is also the common subunit of two different MutL-related complexes and the phenotypes of individuals or mice with mutations in MSH2 and MLH1 are indistinguishable. MSH6 is also a tumor suppressor gene, although inactivation of MSH6 yields a slightly less severe phenotype than that caused by MSH2 or MLH1 mutations because in MSH6-deficient cells, one class of mismatches, insertions/deletions, apparently are repaired normally. PMS2 is a partner for MLH1, and its deficiency in mice leads to tumor susceptibility, although no GI tumors were observed (23 , 26) . Combining Pms2 with an Apc mutation (27) does indeed result in increased tumor susceptibility in the GI tract. Results presented in this report show that MSH3 also plays a cooperating role, especially with MSH6, in tumorigenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by grants from NIH
(CA67944 to M. Lip. and R. K., CA76329 to W. E., CA84301
to R. K. and W. E., GM50006 to R. D. K., CA 54050
to G. C., and Center Grant CA13330 to Albert Einstein College of
Medicine). 
2 To whom requests for reprints should be
addressed, at Department of Molecular Genetics, Albert Einstein College
of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone:
(718) 430-2069; Fax: (718) 430-8776; E-mail: kucherla{at}aecom.yu.edu
3 The abbreviations used are: HNPCC, hereditary
non-polyposis colon cancer; MMR, mismatch repair; ES, embryonic stem;
RT-PCR, reverse transcription-PCR; GI, gastrointestinal.
4 A. Umar and T. Kunkel, unpublished data.
Received 10/27/99. Accepted 12/23/99.
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contain the number of extra nucleotides that
accompany the symbol. Substrates are designated with a
3' when the nick is in the (-) strand at the
AvaII site (position -264), or with a 5'
when the nick is in the (-) strand at the Bsu36 I site
(position +276). The nucleotide position of the mismatch or unpaired
bases in the lacZ
