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Departments of Microbiology and Immunology [T. B., T. S., D. R., S. G., C. M. C., R. F.] and Pathology and Cell Biology [A. B., A. J. K.], Kimmel Cancer Institute, Thomas Jefferson University and Medical College, Philadelphia, Pennsylvania 19107; SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406 [D. R., C. S., J. B.]; and ABL-Basic Research Program, Frederick Cancer Research and Development Center, Frederick, Maryland 21702 [T. C.].
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Introduction |
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Germ-line mutations of hMSH2, hMSH6, hMLH1, and hPMS2 result in a common cancer syndrome, hereditary non-polyposis colorectal cancer (Lynch syndrome), where predisposition to colorectal, endometrial, and other neoplasms is inherited in a dominant pattern (9, 10, 11, 12, 13) . hPMS1 has also been reported to predispose to colorectal cancer (11) . However, with the exception of a single apparent germ-line mutation, there does not appear to be further evidence of its involvement in colorectal or any other cancers. Furthermore, the nearest yeast homologues to hPMS1 are MLH2 and MLH3, which appear to play little or no role in mismatch repair, and mice deleted for PMS1 are not predisposed to develop tumors (14 , 15) . Thus, the role of hPMS1 appears to be significantly different from hMSH2, hMSH3, hMSH6, hMLH1, and hPMS2.
Recently, another human MutS homologue, hMSH4, has been identified (16) . High levels of hMSH4 transcript were found in testis, whereas significantly lower levels were found in ovary. No distinctive hybridization signal was obtained in any other tissues tested. This finding appears to reflect the function of the Saccharomyces cerevisiae MSH4, which is specific for meiosis, is associated with chromosomes during pachytene, and appears to facilitate crossing-overs (17) . Thus, mutation of msh4 in S. cerevisiae leads to homologous nondisjunction in meiosis I and spore inviability. However, the yeast msh4 does not display any mismatch repair defects in either vegetative or meiotic cells (17) . Interestingly, the S. cerevisiae MSH4 protein appears to form a heterodimeric complex with another yeast MutS homologue, MSH5 (18) , and this interaction has been shown to be insensitive to alteration of the consensus adenine nucleotide binding domain. Furthermore, neither MSH4 nor MSH5 interacts with MSH2 or MSH6, suggesting that MSH4 and MSH5 constitute a class of MutS homologue that are functionally different from the proteins that participate in mismatch repair (18) .
The identification of a human MSH5 was published while the manuscript was under review (19) . Here, we have also identified the human MSH5 gene (hMSH5)3 and demonstrate its interaction with hMSH4, but not with hMSH2, hMSH3, or hMSH6. We additionally show a high level of transcript in testis and immunohistochemical expression of the hMSH5 protein during a phase of spermatogenesis starting after early primary spermatocytes and ending with elongated spermatids. These results suggest that hMSH5 may play a role in the development of germ cells.
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Materials and Methods |
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The hMSH4 clone was obtained from a human testis cDNA (Clontech) by PCR with subsequent ligation into the pCR2.1 vector (TA cloning kit; Invitrogen, San Diego, CA). Primer sequences were: outer PCR: forward, 5'-GGA AGG TTT GGG AGG ATG CTG AGG-3'; reverse, 5'-ATT GTG ATT ATT CTT CAG TCT T-3'; nested PCR: forward, 5'-ATC TCG AGA TGC TGA GGC CTG AG-3'; reverse, 5'-GCG CTA GCT TAT TCT TCA GTC TTT TC-3'. The hMSH4 clone was confirmed by complete double strand sequencing of both strands and found to contain a deletion of a C in codon 18 and an insertion of a G in codon 20, resulting in a V19S and V20S, as well as a G 
A at nucleotide 1219, resulting in an E407K amino acid substitution compared to the published sequence (numbered starting with the A in the ATG initiator codon). The sequences found in the original report were never obtained from several different template cDNAs. In addition, we have found an apparent polymorphism at codon 368 (CGC AGA) that does not alter the coding Arg.
Chromosomal Mapping of hMSH5.
PCR reactions were performed using the primers described above, respectively, to screen the Genebridge4 Radiation Hybrid Panel (22)
. Thirty-five cycles were performed with an annealing temperature of 60°C for 30 s, followed by 72°C for 1 min. Fragments were visualized by agarose gel electrophoresis, and data were submitted to the Whitehead Institute/MIT Center for Genome Research for final analysis.
Northern Blotting.
Three multiple tissue Northern blots containing poly A+ RNA of a total of 23 different human tissues were purchased from Clontech. Fifty ng of a full-length hMSH5 cDNA and a ß-actin cDNA control were radiolabeled with [
-32P] dCTP by random primed labeling (Boehringer Mannheim, Mannheim, Germany), and the Northern Blots were hybridized according to the manufacturer’s instructions. Alternatively, a 596-bp fragment was obtained by PCR with the forward primer 5'-CTG GAC GTC ATT CAG TTT and the reverse primer 5'-CAG CTC CTT GGT TCG GGC ACT ACG-3' and used as a probe. The blots were washed in 0.3 M NaCl-30 mM sodium citrate, pH 7.0; 0.05% SDS at room temperature for a total of 60 min, and at 50°C in 15 mM NaCl-1.5 mM sodium citrate, pH 7.0; 0.1% SDS for a total of 40 min. PhosphoImager screens were exposed for 1 day. A 2.5–2.6-kb transcript was detected at a high level in testis. Tissues with significantly lower expression levels are bone marrow, lymph nodes, ovary, brain, and spinal cord.
Antibodies.
Five different 15-mer peptides were synthesized that correspond to predicted immunogenic regions of the hMSH5 protein and conjugated to hemocyanin; polyclonal antibodies were raised in rabbits (H.T.I. Bio-Products, Ramona, CA). Clone C934-2 was found to be most sensitive and specific in Western Blot experiments and was purified over a protein A column for Western analysis. Further affinity purification of the antibody was performed using a crude lysate of Sf9 insect cells overexpressing hMSH5 protein. hMSH5 protein lysate was separated by SDS-PAGE and transferred to nitrocellulose, and the hMSH5-specific region was excised and used to affinity purify the antibody (23)
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Immunohistochemistry.
Sections (5 µm) of formalin-fixed and paraffin-embedded tissues were cut onto Neoprene-coated slides (Aldrich Chemicals, Milwaukee, WI). After deparaffinization including a 30-min Methanolic peroxide block for endogenous peroxidase activity (Leica Autostainer, Leica, Deerfield, IL), the slides were microwaved in 200 ml of Chem.Mate H.I.E.R buffer, pH 5.5–5.7 (Ventana Medical Systems, Tucson, AZ) at high energy for 5 min (Panasonic Microwave NN-5602A, Franklin PK, IL). Fifty ml of H2O were replaced for an additional microwaving step of 4 min at high energy.
Immunostaining with the catalyzed signal amplification system (DAKO, Carpinteria, CA) was performed according to the manufacturer’s instructions and incubation with protein A, and hMSH5 specific affinity-purified polyclonal antibody took 50 min at room temperature at a concentration of 1:800 or 1:2000 with the hMSH2 polyclonal antibody (Ab-3; Oncogene Research Products, Cambridge, MA), respectively. For counterstaining with Harris Hematoxylin (Surgipath, Richmond, IL), the Leica Autostainer was used.
GST Fusion Protein Interaction Assay.
Five hundred µl of 5 ml of overnight starter cultures of pGEX-Fusion proteins with hMSH2, hMSH3, hMSH4, hMSH5, and hMSH6, as well as pGEX without insert (negative control), were inoculated in 50 ml of Luria broth with 50 µg/ml ampicillin and grown to an A600 of 0.5. Protein expression was induced with 0.1 mM isopropyl-1-thio-ß-D-galactopyranoside for 2 h at 30°C. The cells were pelleted and resuspended in 750 µl of PBS containing protease inhibitors. A 10-min digestion on ice with 1 mg/ml Lysozyme followed. After the addition of 0.2% Triton X-100 and 1 mM DTT, the lysate was snap frozen in liquid nitrogen and thawed twice. A DNAseI digest was performed (Boehringer Mannheim) at a concentration of 200 units/ml for 30 min on ice, and the cell debris was spun down at 14,000 rpm at 4°C for 30 min. Equal amounts of the lysates of the different fusion proteins or with GST alone as a negative control were incubated on a rocking platform for 1 h at 4°C with 2 mg of glutathione-agarose beads (Sigma Chemical Co., St. Louis, MO) each, which had been preswollen in PBS with proteinase inhibitors for 1 h at room temperature. The beads were washed three times with 500 µl of interaction buffer [20 mM Tris · HCl (pH 7.5), 10% glycerol, 150 mM NaCl, 0.1% Tween 20, 5 mM EDTA, 1 mM DTT, 0.75 mg/ml BSA (Amresco, Solon, OH), and proteinase inhibitors] and subsequently incubated in interaction buffer for 1 h at 4°C on a rocking platform.
IVTTs were performed on 1 µg of each hMSH2, hMSH3, hMSH5, and hMSH6 inserts in pET vectors and on hMSH4 in pCR 2.1 with the TNT-coupled reticulocyte lysate system (Promega Corp., Madison, WI) according to the manufacturer’s protocol incorporating 40 µCi of [35S]methionine. Five µl of the IVTTs were added to 500 µl of beads in interaction buffer and incubated for 1 h at 4°C on the rocking platform. After three final washing steps, the supernatant was removed carefully, and the beads were resuspended in 35 µl of 2x Spear’s, boiled for 5 min, and spun for 5 min at 14000 rpm. Fifteen µl of each reaction were loaded on an 8% SDS-PAGE Gel (Bio-Rad MiniProtean II) and run for about 90 min at 135 V. Molecular Dynamics PhosphoImager screens were exposed to the dried gels for 1 day.
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with a predicted Mr 97,000. NH2-terminal to the Start-ATG was one STOP codon, and the entirety of the sequence was further confirmed by 5'-rapid amplification of cDNA ends. The nucleotide sequence differs from the report published previously (19)
because we found a C T at nucleotide position 2292, which would result in a leucine (CTT) instead of a valine (CCT) in the amino acid sequence.
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MSH5 Defines a New Family of MutS Homologue involved in Sporulation and Meiosis.
Of all eukaryotic and prokaryotic MutS homologues, the b29 clone was found to be most closely related to ceMSH5 (29% identity) and scMSH5 (25% identity) with a region encompassing the adenine nucleotide binding domain displaying 
60% identity between these homologues. Thus, the gene was called hMSH5. In the family of MutS homologues, the next closest relatives are the MSH2 cousins, whereas hMSH3 and hMSH6 appear to be derived from a second branch of the human MutS homologue (Fig. 2A)
and more closely related to the bacterial MutS proteins. In the present alignment, the MSH4 cousins appear the most divergent. Interestingly, there is a cohort of MutS homologues found in a subset of bacteria that are homologous to hMSH5 but largely unrelated to their postreplication mismatch repair cousins. There do not appear to be any distinguishing characteristics between these bacteria that would clearly shed light on the function of these MutS homologues and the MSH5 proteins. As with other MutS homologues, the most highly conserved region surrounds the adenine nucleotide binding domain, although the MSH5 cousins appear to be the most divergent (Fig. 2B)
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. These results appear to correspond to the finding in yeast, where MSH5 appeared meiosis specific (24)
. The size of the transcript corresponds well to the length of the cDNA sequence, which is 2.5 kb. hMSH5 transcript expression was also observed in bone marrow, lymph node, brain, spinal cord, trachea, and ovary (Fig. 3A)
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. Western blot analysis revealed expression of hMSH5 in testis and tonsil tissue and at very low levels in two T- and B-cell tumor lines (Jurkat, CEM, Daudi, and GM1500; data not shown). It is important to note that the Western signal in these tissues contained several low molecular weight protein band(s) that were also found when a number of secondary detection systems were used alone. These results suggested that the low molecular weight bands not identifiable as hMSH5 were the result of nonspecific interaction between the secondary detection systems and that a high resolution secondary detection system was required to enhance specificity of the antibody. Such a system was developed for immunohistochemical studies (see "Materials and Methods"), but the same system is not amenable for use in Western analysis. The presence of hMSH5 transcript in tissues where B- and T-cells develop as well as expression in the T- and B-cell lines may suggest a relationship to other cellular development processes that may also include recombination events. However, it is also possible that the low levels of hMSH5 protein expression in the B- and T-cell lines could result from the fact that the cell lines are derived from hematological malignancies and thus do not represent normal B- and T-cell precursors or other undefined factors. Fresh bone marrow from a healthy person for Western analysis or immunohistochemistry could not be obtained for these studies. The presence of hMSH5 transcript in brain, spinal cord, and trachea is unclear.
Western analysis suggested that the purified polyclonal antibody C934-2 derived from a synthetic peptide might be useful in immunohistochemical (IHC) studies. For these studies, we used catalyzed signal amplification (see "Materials and Methods"). Specificity was determined by comparing samples prepared by incubation, with or without preimmune primary antibody, to samples incubated with the hMSH5 primary antibody. Testis tissues were obtained from surgical resections and contained evidence of testicular tumors. However, we confined our examination of hMSH5 expression to tissue regions that displayed clear evidence of full sperm maturation. IHC suggested strong nuclear positivity in spermatids in statu nascendi, within round and elongated spermatids (S3), whereas all the phases of spermatogenesis up to early primary spermatocytes as well as the spermatozoa themselves were completely negative (Fig. 4, A–D)
. This observation suggests that hMSH5 plays a specific role in the processes associated with the late first or the second meiotic division (Fig. 4I)
. Because the testicular histology of the surgical orchiectomy specimens was not entirely normal, we cannot rule out abnormal expression of hMSH5 in these testicular samples. In the samples shown, histological examination reveals the presence of discrete lymphocytic infiltrates and occasional intratubular neoplasia (scattered single tumor cells in the tubules that are characterized by a pale large cytoplasm and a large round nucleus). However, spermatogenesis in these samples appeared to be functioning sufficiently to produce mature sperm cells, and a number of tubules were found where there was no evidence of neoplasia (Fig. 4A)
. Furthermore, staining of spermatids is evident in all of the tubules that appear largely normal based on the presence of all stages of spermatogenesis. Textbook examples of normal tubules would show the cell types of spermatogenesis filling the entire tubule. However, entirely normal fresh testis tissue could not be obtained, and IHC was not possible in autopsy material because of widespread protein degradation.
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. The Sertoli cells exhibit a very faint nuclear staining with the hMSH2 antibody (Fig. 4E)
. The hMSH2 expression in tissue is clearly correlated with proliferation in general, which is exemplified in this study by the strong nuclear positivity in the seminoma (Fig. 4F)
. In addition, tissues that were positive for hMSH2 were also positive for the proliferation marker Ki67 (data not shown). hMSH5 protein expression is completely negative in the seminoma as well as in other testicular malignancies (e.g., embryonal cell carcinoma, mature and immature teratoma; data not shown; Fig. 4G
). Note that expression of hMSH5 is absent in dividing spermatogonium A (see M, Fig. 4D
), suggesting that expression is not induced during mitosis.
Protein Interaction Studies.
Because the human MutS homologue hMSH2, hMSH3, and hMSH6 are known to act as heterodimers, interaction studies of hMSH5 with hMSH2, hMSH3, hMSH4, and hMSH6 were performed. In these studies, GST-fusion proteins (GST) containing hMSH(x) "bait" were incubated with 35S-labeled IVTT hMSH(y) "prey." Specific interactions were detected as labeled proteins that precipitated with the GST-hMSH(x) when glutathione-agarose beads were introduced. As positive controls, we demonstrate that hMSH2 interacts strongly with hMSH3 either as an IVTT-hMSH2 with GST-hMSH3 (Fig. 5A)
or a GST-hMSH2 with IVTT-hMSH3 (Fig. 5B)
. Similarly, hMSH2 strongly interacts with hMSH6, either as an IVTT-hMSH2 and GST-hMSH6 (data not shown, Ref. 7
) or as a GST-hMSH2 and IVTT-hMSH6 (Fig. 5E)
. The negative controls are lysates expressing the GST moiety alone, which do not significantly interact with any of the IVTT-hMSH(y) (Fig. 5)
. Interaction was confirmed by densitometric quantitation, which suggested at least a 10-fold difference in activity (Fig. 5)
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. In the reverse experiment, GST-hMSH5 displayed no interaction above background when incubated with IVTT-hMSH2, IVTT-hMSH3, and IVTT-hMSH6 (Fig. 5C)
. However, there appears to be a significant interaction between GST-hMSH5 with IVTT-hMSH4, which results in a distinct band that is completely absent in the negative control (Fig. 5C)
. Different reaction buffers (phosphate buffer and variations in the concentrations of NaCl, Tween 20, and BSA) did not alter the background or the interaction (data not shown). For comparison, the levels of IVTT expression used in these experiments are shown in Fig. 5F
. We have found that the levels of GST-MSH(X) fusion protein are always in vast excess of the IVTT material, suggesting that specific interaction is related to the amount of IVTT material that associates with the GST-fusion protein (7)
. Taken together, these results suggest that hMSH5 specifically interacts with hMSH4 alone. |
Discussion |
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We also observed low level expression of hMSH5 mRNA in a few other tissues. The most interesting are the bone marrow and lymph node, where T-cell and B-cell development takes place. At present, we have been unable to examine the expression of the hMSH5 protein in these tissues because normal tissues could not be obtained. However, we were still able to observe some full-length hMSH5 protein expressed in a tonsil surgical sample (a repository of developing B cells). These results suggest that hMSH5 may play a role in both B- and perhaps T-cell development and that defects in hMSH5 might result in hematological defects.
hMSH5 appears to specifically interact with hMSH4. No interaction with hMSH5 above background was observed for hMSH2, hMSH3, or hMSH6. Likewise, hMSH4 does not seem to interact with hMSH2, hMSH3, or hMSH6. Thus, it is likely that the hMSH4-hMSH5 heterodimer is specific and constitutes a functional interaction that is separate from hMSH2-hMSH3 and hMSH2-hMSH6 heterodimers. Because this heterodimer constitutes the third identified interaction between human MutS homologues as well as the fact that this heterodimer appears to function very differently from the progenitor bacterial MutS, the MutS (greek letter) nomenclature adopted by others would seem both inappropriate and nondescript (5)
. However, based on the conservation of the adenine nucleotide binding and hydrolysis domain, it is likely that the hMSH4-hMSH5 heterodimer also functions as a molecular switch (8)
. Although the control of the hMSH2-hMSH3 and hMSH2-hMSH6 molecular switches is mismatch provoked ADP ATP exchange, the molecular structure that controls the hMSH4-hMSH5 switch is unknown. Purification of the hMSH4-hMSH5 heterodimeric protein is likely to provide an answer to this question.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by Grants CA56542 and CA67007 (to R. F.). T. B. was supported by Grant Bo/1445-2 from the Deutsche Forschungsgemeinschaft. 
2 To whom requests for reprints should be addressed, at Thomas Jefferson University, Jefferson Medical College, Kimmel Cancer Institute, 233 South 10th Street, Philadelphia, PA 19107. Phone (215) 503-1345; Fax: (215) 923-1098; E-mail: rfishel{at}hendrix.jci.tju.edu
3 Sequence data from have been deposited with the GenBank Data Library under Accession Number AF034759.
4 The abbreviations used are: EST, expressed sequence tag; IVTT, in vitro transcription and translation; IHC, immunohistochemistry; GST, glutathione S-transferase.
Received 7/17/98. Accepted 1/ 5/99.
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