HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phung, Q. H. Articles by Gearhart, P. J. Search for Related Content PubMed PubMed Citation Articles by Phung, Q. H. Articles by Gearhart, P. J.

Cutting Edge: Hypermutation in Ig V Genes from Mice Deficient in the MLH1 Mismatch Repair Protein

Quy H. Phung^*,, David B. Winter^*, Rudaina Alrefai^* and Patricia J. Gearhart^1,*

^* Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and Graduate Program in Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
During somatic hypermutation of Ig V genes, mismatched nucleotide substitutions become candidates for removal by the DNA mismatch repair pathway. Previous studies have shown that V genes from mice deficient for the MSH2 and PMS2 mismatch repair proteins have frequencies of mutation that are comparable with those from wild-type (wt) mice; however, the pattern of mutation is altered. Because the absence of MSH2 and PMS2 produced different mutational spectra, we examined the role of another protein involved in mismatch repair, MLH1, on the frequency and pattern of hypermutation. MLH1-deficient mice were immunized with oxazolone Ag, and splenic B cells were analyzed for mutations in their VOx1 light chain genes. Although the frequency of mutation in MLH1-deficient mice was twofold lower than in wt mice, the pattern of mutation in Mlh1^-/- clones was similar to wt clones. These findings suggest that the MLH1 protein has no direct effect on the mutational spectrum.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Two types of somatic mutation mechanisms exist in B lymphocytes. One mechanism is spontaneous mutation, which is common to all cells and is caused by the misincorporation of nucleotides or slippage of DNA polymerase during DNA replication of chromosomes. Most of the replication errors are then removed by the mismatch repair pathway to ensure high fidelity of DNA replication. Thus, the frequency of spontaneous mutation after correction is 10^-8 mutations per base pair, and this frequency increases several fold when mismatch repair proteins are deficient 1, 2, 3, 4, 5 . The other mechanism is hypermutation, which is unique to B cells and is caused by unknown enzymes. The frequency of hypermutation is 10^-2 mutations/base pair, and mutation occurs in a 2-kb region around rearranged V genes (reviewed in 6 .

Recently, there has been a great deal of interest in studying hypermutation in V genes from mice deficient in the mismatch repair pathway 7, 8, 9, 10 . Studies from several labs have shown that mice deficient for the MSH2 and PMS2 mismatch repair proteins have hypermutation 11, 12, 13, 14, 15 ; this finding is in contrast to an earlier report by Cascalho et al. 16 . The frequency of mutation in the repair-deficient mice was either the same or several fold lower than in wild-type (wt)² mice, depending upon the type of exposure to Ag. After deliberate exposure by immunization with Ag, rearranged V and V genes from splenic B cells from MSH2- and PMS2-deficient mice had the same frequencies of mutation as repair-proficient mice (1% mutations per base pair) 11, 12, 13, 14 . After chronic exposure to environmental gut-associated Ags, rearranged V_H genes from Peyer’s patch B cells from MSH2- and PMS2-deficient mice had a three- to fivefold lower frequency of mutation compared with wt mice 14, 15 . The diminished response in the chronically stimulated cells may be due to early cell death before the V genes can undergo many rounds of mutation 14, 15 . Thus, a lack of DNA repair allows spontaneous mutations to persist in the overall genome; consequently, when such mutations occur in genes critical for cell survival, the cell dies.

The pattern of mutation from MSH2- and PMS2-deficient mice has also been examined. V genes from Msh2^-/- mice had a greatly increased number of mutations at G and C nucleotides compared with A and T nucleotides 11, 12, 14, 15 . V genes from Pms2^-/- mice had a greater number of tandem mutations, which was confirmed by the inability of Pms2^-/- cell extracts to repair adjacent mutations on artificial substrates 13 . This altered spectrum of mutation in the mismatch repair-deficient mice compared with wt mice suggests that mismatch repair proteins remove some of the mutations before DNA replication. However, this process is inefficient, perhaps because the mismatch repair pathway is unable to deal with the excessively large number of mismatches generated by the hypermutation mechanism.

In addition to MSH2 and PMS2, other proteins such as MSH6 and MLH1 participate in the mismatch repair pathway, as shown in Fig. 1. Because the absence of MSH2 and PMS2 produced different mutational spectra in V genes, these other proteins may also be involved in removing mismatches generated during hypermutation. For example, Mlh1^-/-, Pms2^-/-, and Msh2^-/- mice each have distinct phenotypes for reproduction and tumors 5, 17, 18, 19, 20, 21 , and they may possess different mutational patterns as well. Therefore, we examined the role of one of the proteins, MLH1, in hypermutation. MLH1, along with PMS2, binds to the MSH2-MSH6 protein complex that recognizes base-base mismatches. MLH1-deficient mice are infertile because of arrest at the pachytene stage of meiosis, have microsatellite instability, and are susceptible to adenocarcinomas 5, 17, 18 . Mice were immunized, and mutations in V genes were analyzed.

View larger version (45K): [in this window] [in a new window]   FIGURE 1. Mammalian DNA mismatch repair. A heterodimer of MSH2 and MSH6 proteins recognizes base-base mismatches and extrahelical loops of 1 or 2 nt. The complex subsequently combines with a heterodimer of PMS2 and MLH1. Repair occurs after the newly synthesized strand is nicked, exonuclease removes the mismatch, and DNA polymerase fills in the gap.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

MLH1-deficient mice (obtained from R. M. Liskay, Portland, OR) were generated by insertion of an hprt minigene to replace a 2.5-kb fragment of exon 4 in Mlh1 17 . Four Mlh1^-/- mice that had been bred onto a C57BL/6 and AB-129 background were given a primary i.p. injection of 50 µg of phenyloxazolone coupled to chicken serum albumin (a gift of C. Milstein, Cambridge, U.K.) in CFA. After 1 mo, the mice were administered a secondary injection of 50 µg of Ag in IFA. Mice were sacrificed after 4 days, and spleens were removed. B cells that bound to phycoerythrin-labeled B220 and fluorescein-labeled GL7 22 (PharMingen, San Diego, CA) as well as peanut agglutinin were isolated by flow cytometry.

DNA cloning and sequencing

DNA from 50,000 cells was isolated by proteinase K digestion and phenol/chloroform extraction. The VOx1 gene segment rearranged to the J5 gene segment was amplified through 30 rounds of PCR with Pfu polymerase (Stratagene, La Jolla, CA) using a primer specific for the leader sequence on the 5' side of the gene and a primer specific for the J5 gene segment on the 3' side. Part of the reaction (1/25th) was then subjected to another 30 rounds of PCR using nested primers with restriction sites for cloning the amplified product into M13 bacteriophage. DNA containing the ligated M13 vector was transformed into JM101 bacteria by electroporation and immediately poured onto agarose plates to obtain unique libraries. M13 plaques were screened for inserts by hybridization to a VOx1 probe, and positive clones were sequenced.

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mlh1^-/- V genes have a low frequency of mutation

Mutation was analyzed in a defined V gene, VOx1 23 , from splenic B cells from immunized mice. Some 52 clones were sequenced for 466 bp, which included 190 nucleotides (nt) of 5' intron DNA between the leader and V gene segment and 276 nt of coding region DNA. Approximately 31 of 52 Mlh1^-/- clones (60%) had mutations. The same percentage of clones had mutations in Mlh1^+/+ C57BL/6 mice 13 . Of the mutated clones, 29 were distinct in that they either had different sequences at the V-J junction or had unique substitutions that were not shared by other clones. These clones are listed in Table I in ascending order of mutations per clone, ranging from 1 to 18. There were 90 base substitutions and 3 single nt insertions and deletions, giving an average frequency of 0.7% mutations/base pair. This frequency is comparable with the 0.9% mutations/base pair observed in Pms2^-/- clones (Fig. 2) but is lower than the 1.4% mutations/base pair in C57BL/6 clones and the 1.3% mutations/base pair in Msh2^-/- clones 12, 13, 14 . The twofold lower frequency in the Mlh1^-/- clones was due to a predominance of sequences with less than four mutations, as was the case for Pms2^-/- clones 13 . As proposed by Frey et al. 14 and Rada et al. 15 , mismatch repair-deficient mice likely have chromosomal alterations because of a lack of repair of spontaneous mutations in all the genes. This genomic instability becomes fatal when it affects those genes that control growth and division, so that rapidly dividing B cells die before an accumulation of large numbers of mutations in their V genes. In support of this hypothesis, Vora et al. 24 have recently reported that Msh2^-/- mice have smaller germinal centers with more apoptosis than wt mice. The lower frequencies of mutation in V genes from immunized MLH1- and PMS2-deficient mice suggest that the absence of these two mismatch repair proteins is more detrimental to B cell survival than the absence of MSH2.

View this table: [in this window] [in a new window]   Table I. Mutations in VOx1 genes from MLH1-deficient mice1

View larger version (17K): [in this window] [in a new window]   FIGURE 2. Distribution of mutations in the rearranged VOx1 gene from mismatch repair-proficient and -deficient mice. A diagram of the flanking and coding regions that were sequenced is shown at the bottom of the figure; complementarity-determining regions are indicated by striped boxes. Numbers on the abscissa refer to the nucleotide distance, with "1" representing the first base in the V gene and negative numbers representing the 5' flanking region. Bars depict the frequency of mutation per 10-nt increments. Data for C57BL/6, Msh2-/-, and Pms2-/- clones were obtained from References 12 and 13.

Nucleotide substitutions in Mlh1^-/- clones are similar to wt clones

The types of substitutions in different mismatch repair-deficient mice are compared in Table II. If hypermutation occurs nondiscriminatingly on each nucleotide, equal amounts of mutation should occur at A:T pairs compared with G:C pairs. This was generally the case for VOx1 genes from C57BL/6, Pms2^-/-, and Mlh1^-/- mice. However, as reported previously 11, 12, 14, 15 , most of the mutations in Msh2^-/- clones occurred at G and C nucleotides. Thus, MSH2 behaves independently from PMS2 and MLH1 in repairing mismatches generated by the hypermutation mechanism.

View this table: [in this window] [in a new window]   Table II. Types of substitutions in VOx1 genes1

Tandem mutations of two in a row were of particular interest, because VOx1 genes from Pms2^-/- mice had a greatly increased frequency of adjacent mutations compared with those from C57BL/6 and Msh2^-/- mice 12, 13 . Because the MLH1 protein pairs with PMS2 at the same step in mismatch repair (Fig. 1), Mlh1^-/- clones may also have more tandem mutations. There were three tandem mutations in the Mlh1^-/- clones; these mutations are underlined in Table I. The observed numbers of tandems in each of the repair-deficient strains are summarized in Table III and compared with the expected numbers. Expected numbers were calculated according to the probability that two mutations will randomly occur next to each other in clones with a length of 466 nt 13 . Only the Pms2^-/- clones had a significant increase in tandem mutations (p < 10^-6) as determined by exact Poisson calculations regarding whether the observed and expected values were equal for each group. This observation suggests that the PMS2 protein acts independently of MLH1 in correcting adjacent mutations put in by the hypermutation mechanism.

Although MSH2, PMS2, and MLH1 are all required for mismatch repair, mice deficient in these proteins have distinct phenotypes for several biological mechanisms, suggesting that they can function independently. In the mechanisms of reproduction and recombination, MSH2-deficient male and female mice are fertile 19, 20 , PMS2-deficient males are sterile but females are fertile 21 , and MLH1-deficient males and females are sterile 17, 18 . The yeast equivalents of PMS2 and MSH2 also have different effects in suppressing meiotic and mitotic recombination 26, 27 . Thus, these three proteins have independent functions during the recombination of chromosomes. In the mechanism of tumor suppression, PMS2- and MSH2-deficient mice predominantly have lymphomas, whereas MLH1-deficient mice mostly have intestinal adenomas and adenocarcinomas 5, 19, 20, 21 . Furthermore, humans with hereditary nonpolyposis colorectal cancer have mutations predominantly in Msh2 and Mlh1 genes and rarely in Pms2 genes 28 . These different tumor spectra suggest that PMS2 and MLH1 have overlapping but nonidentical functions. In the mechanism of DNA repair, MSH2-deficient human cells cannot remove oxidative damage from the transcribed strand of DNA, whereas MLH1-deficient cells can remove the damage; this observation suggests a differential involvement of the two proteins in transcription-coupled repair 29 .

In the mechanism of hypermutation, we propose that MSH2, PMS2, and MLH1 proteins, although not required to generate or fix hypermutation in V genes, have independent functions for removing a portion of the mismatches. The altered spectrum of mutations in V genes from repair-deficient mice suggests that MSH2 removes mismatches at G and C nucleotides, PMS2 removes tandem mismatches, and MLH1 has no discernible effect. This different pattern of mutation suggests that the hypermutation mechanism frequently generates substitutions opposite G and C nucleotides and produces tandem mutations, which may occur during short-patch repair 30 .

	Acknowledgments

 
We thank R. Liskay for the Mlh1^-/- mice, F. Chrest for flow cytometry, and R. Tarone for statistical analyses. We also thank A. Walley, J. Blumenthal, and L. Diamond for assistance in sequencing. We acknowledge V. Bohr for enthusiastic support and V. Bohr, R. Wood, and N. Lipinski for critical comments on the manuscript.

	Footnotes

 
¹ Address correspondence and reprint requests to Dr. Patricia J. Gearhart, Laboratory of Molecular Genetics, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail address:

² Abbreviations used in this paper: wt, wild type; nt, nucleotide(s).

Received for publication November 24, 1998. Accepted for publication January 8, 1999.

	References

Top Abstract Introduction Materials and Methods Results and Discussion References

 

1. Malkhosyan, S., A. McCarty, H. Sawai, M. Perucho. 1996. Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. Mutat. Res. 316:249.[Medline]
2. Glaab, W. E., K. R. Tindall. 1997. Mutation rate at the hprt locus in human cancer cell lines with specific mismatch repair-gene defects. Carcinogenesis 18:1.[Abstract/Free Full Text]
3. Narayanan, L., J. A. Fritzell, S. M. Baker, R. M. Liskay, P. M. Glazer. 1997. Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. Proc. Natl. Acad. Sci. USA 94:3122.[Abstract/Free Full Text]
4. Andrew, S. E., M. McKinnon, B. S. Cheng, A. Francis, J. Penney, A. H. Reitmair, T. W. Mak, F. R. Jirik. 1998. Tissues of MSH2-deficient mice demonstrate hypermutability on exposure to a DNA methylating agent. Proc. Natl. Acad. Sci. USA 95:1126.[Abstract/Free Full Text]
5. Prolla, T. A., S. M. Baker, A. C. Harris, J.-L. Tsao, X. Yao, C. E. Bronner, B. Zheng, M. Gordon, J. Reneker, N. Arnheim, et al 1998. Tumour susceptibility and spontaneous mutation in mice deficient in Mlh1, Pms1, and Pms2 DNA mismatch repair. Nat. Genet. 18:276.[Medline]
6. Somatic hypermutation of immunoglobulin genes. 1998. Immunol. Rev. 162.
7. Kelsoe, G.. 1998. V(D)J hypermutation and DNA mismatch repair: vexed by fixation. Proc. Natl. Acad. Sci. USA 95:6576.[Free Full Text]
8. Kim, N., U. Storb. 1998. The role of DNA repair in somatic hypermutation of immunoglobulin genes. J. Exp. Med. 187:1729.[Free Full Text]
9. Wiesendanger, M., M. D. Scharff, W. Edelmann. 1998. Somatic hypermutation, transcription, and DNA mismatch repair. Cell 94:415.[Medline]
10. Wood, R. D.. 1998. Knockouts still mutating after first round. Curr. Biol. 8:R757.[Medline]
11. Jacobs, H., Y. Fukita, G. T. J. van der Horst, J. de Boer, G. Weeda, J. Essers, N. de Wind, B. P. Engelward, L. Samson, S. Verbeek, et al 1998. Hypermutation of immunoglobulin genes in memory B cells of DNA repair-deficient mice. J. Exp. Med. 187:1735.[Abstract/Free Full Text]
12. Phung, Q. H., D. B. Winter, A. Cranston, R. E. Tarone, V. A. Bohr, R. Fishel, P. J. Gearhart. 1998. Increased hypermutation at G and C nucleotides in immunoglobulin variable genes from mice deficient in the MSH2 mismatch repair protein. J. Exp. Med. 187:1745.[Abstract/Free Full Text]
13. Winter, D. B., Q. H. Phung, A. Umar, S. M. Baker, R. E. Tarone, K. Tanaka, R. M. Liskay, T. A. Kunkel, V. A. Bohr, P. J. Gearhart. 1998. Altered spectra of hypermutation in antibodies from mice deficient for the DNA mismatch repair protein PMS2. Proc. Natl. Acad. Sci. USA 95:6953.[Abstract/Free Full Text]
14. Frey, S., B. Bertocci, F. Delbos, L. Quint, J.-C. Weill, C.-A. Reynaud. 1998. Mismatch repair deficiency interferes with the accumulation of mutations in chronically stimulated B cells and not with the hypermutation process. Immunity 9:127.[Medline]
15. Rada, C., M. R. Ehrenstein, M. S. Neuberger, C. Milstein. 1998. Hot spot focusing of somatic hypermutation in MSH2-deficient mice suggests two stages of mutational targeting. Immunity 9:135.[Medline]
16. Cascalho, M., J. Wong, C. Steinberg, M. Wabl. 1998. Mismatch repair co-opted by hypermutation. Science 279:1207.[Abstract/Free Full Text]
17. Baker, S. M., A. W. Plug, T. A. Prolla, C. E. Bronner, A. C. Harris, X. Yao, D. Christie, C. Monell, N. Arnheim, A. Bradley, T. Ashley, R. M. Liskay. 1996. Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat. Genet. 13:336.[Medline]
18. Edelmann, W., P. E. Cohen, M. Kane, K. Lau, B. Morrow, S. Bennett, A. Umar, T. Kunkel, G. Cattoretti, R. Chaganti, et al 1996. Meiotic pachytene arrest in MLH1-deficient mice. Cell 85:1125.[Medline]
19. De Wind, N., M. Dekker, A. Berns, M. Radman, H. te Riele. 1995. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82:321.[Medline]
20. Reitmair, A. H., R. Schmits, A. Ewel, B. Bapat, M. Redston, A. Mitri, P. Waterhouse, H.-W. Mittrucker, A. Wakeham, B. Liu, et al 1995. MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nat. Genet. 11:64.[Medline]
21. Baker, S. M., C. E. Bronner, L. Zhang, A. W. Plug, M. Robatzek, G. Warren, E. A. Elliott, J. Yu, T. Ashley, N. Arnheim, R. A. Flavell, R. M. Liskay. 1995. Male mice defective in the DNA mismatch repair gene PMS2 exhibit abnormal chromosome synapsis in meiosis. Cell 82:309.[Medline]
22. Laszlo, G., K. S. Hathcock, H. B. Dickler, R. J. Hodes. 1993. Characterization of a novel cell-surface molecule expressed on subpopulations of activated T and B cells. J. Immunol. 150:5252.[Abstract]
23. Kaartinen, M., G. M. Griffiths, A. F. Markham, C. Milstein. 1983. mRNA sequences define an unusually restricted IgG response to 2-phenyloxazolone and its early diversification. Nature 304:320.[Medline]
24. Vora, K. A., K. M. Tumas-Brundage, V. M. Lentz, A. Cranston, R. Fishel, T. Manser. 1999. Severe attenuation of the B cell immune response in Msh2-deficient mice. J. Exp. Med. 189:471.[Abstract/Free Full Text]
25. Alzari, P. M., S. Spinelli, R. A. Mariuzza, G. Boulot, R. J. Poljak, J. M. Jarvis, C. Milstein. 1990. Three-dimensional structure determination of an anti-2-phenyloxazolone antibody: the role of somatic mutation and heavy/light chain pairing in the maturation of an immune response. EMBO J. 9:3807.[Medline]
26. Hunter, N., S. R. Chambers, E. J. Lewis, R. H. Borts. 1996. The mismatch repair system contributes to meiotic sterility in an interspecific yeast hybrid. EMBO J. 15:1726.[Medline]
27. Datta, A., A. Adjiri, L. New, G. F. Crouse, S. Jinks-Robertson. 1996. Mitotic crossovers between diverged sequences are regulated by mismatch repair proteins in Saccaromyces cerevisiae. Mol. Cell. Biol. 16:1085.[Abstract]
28. Liu, B., R. Parsons, N. Papadopoulos, N. C. Nicolaides, H. T. Lynch, P. Watson, J. R. Jass, M. Dunlop, A. Wyllie, P. Peltomaki, et al 1996. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat. Med. 2:169.[Medline]
29. Leadon, S. A., A. V. Avrutskaya. 1997. Differential involvement of the human mismatch repair proteins hMLH1 and hMSH2, in transcription-coupled repair. Cancer Res. 57:3784.[Abstract/Free Full Text]
30. Bertocci, B., L. Quint, F. Delbos, C. Garcia, C.-A. Reynaud, J.-C. Weill. 1998. Probing immunoglobulin gene hypermutation with microsatellites suggests a nonreplicative short patch DNA synthesis process. Immunity 9:257.[Medline]

This article has been cited by other articles:

				A. Durandy Immunoglobulin class switch recombination: study through human natural mutants Phil Trans R Soc B, March 12, 2009; 364(1517): 577 - 582. [Abstract] [Full Text] [PDF]

				J. E Sale, C. Batters, C. E Edmunds, L. G Phillips, L. J Simpson, and D. Szuts Timing matters: error-prone gap filling and translesion synthesis in immunoglobulin gene hypermutation Phil Trans R Soc B, March 12, 2009; 364(1517): 595 - 603. [Abstract] [Full Text] [PDF]

				H. Saribasak, D. Rajagopal, R. W Maul, and P. J Gearhart Hijacked DNA repair proteins and unchained DNA polymerases Phil Trans R Soc B, March 12, 2009; 364(1517): 605 - 611. [Abstract] [Full Text] [PDF]

				C.-A. Reynaud, F. Delbos, A. Faili, Q. Gueranger, S. Aoufouchi, and J.-C. Weill Competitive repair pathways in immunoglobulin gene hypermutation Phil Trans R Soc B, March 12, 2009; 364(1517): 613 - 619. [Abstract] [Full Text] [PDF]

				S. Peron, A. Metin, P. Gardes, M.-A. Alyanakian, E. Sheridan, C. P. Kratz, A. Fischer, and A. Durandy Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination J. Exp. Med., October 27, 2008; 205(11): 2465 - 2472. [Abstract] [Full Text] [PDF]

				H. M. Shen, A. Tanaka, G. Bozek, D. Nicolae, and U. Storb Somatic Hypermutation and Class Switch Recombination in Msh6-/-Ung-/- Double-Knockout Mice J. Immunol., October 15, 2006; 177(8): 5386 - 5392. [Abstract] [Full Text] [PDF]

				K. M. McBride, A. Gazumyan, E. M. Woo, V. M. Barreto, D. F. Robbiani, B. T. Chait, and M. C. Nussenzweig Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation PNAS, June 6, 2006; 103(23): 8798 - 8803. [Abstract] [Full Text] [PDF]

				X. Wu, C. Y. Tsai, M. B. Patam, H. Zan, J. P. Chen, S. M. Lipkin, and P. Casali A Role for the MutL Mismatch Repair Mlh3 Protein in Immunoglobulin Class Switch DNA Recombination and Somatic Hypermutation J. Immunol., May 1, 2006; 176(9): 5426 - 5437. [Abstract] [Full Text] [PDF]

				T. M. Wilson, A. Vaisman, S. A. Martomo, P. Sullivan, L. Lan, F. Hanaoka, A. Yasui, R. Woodgate, and P. J. Gearhart MSH2-MSH6 stimulates DNA polymerase {eta}, suggesting a role for A:T mutations in antibody genes J. Exp. Med., February 22, 2005; 201(4): 637 - 645. [Abstract] [Full Text] [PDF]

				A. Martin, Z. Li, D. P. Lin, P. D. Bardwell, M. D. Iglesias-Ussel, W. Edelmann, and M. D. Scharff Msh2 ATPase Activity Is Essential for Somatic Hypermutation at A-T Basepairs and for Efficient Class Switch Recombination J. Exp. Med., October 20, 2003; 198(8): 1171 - 1178. [Abstract] [Full Text] [PDF]

				B. Reina-San-Martin, S. Difilippantonio, L. Hanitsch, R. F. Masilamani, A. Nussenzweig, and M. C. Nussenzweig H2AX Is Required for Recombination Between Immunoglobulin Switch Regions but Not for Intra-Switch Region Recombination or Somatic Hypermutation J. Exp. Med., June 16, 2003; 197(12): 1767 - 1778. [Abstract] [Full Text] [PDF]

				H.-F. Tsai, N. D'Avirro, and E. Selsing Gene conversion-like sequence transfers in a mouse antibody transgene: antigen selection allows sensitive detection of V region interactions based on homology Int. Immunol., January 1, 2002; 14(1): 55 - 64. [Abstract] [Full Text] [PDF]

				Q. Kong and N. Maizels DNA Breaks in Hypermutating Immunoglobulin Genes: Evidence for a Break-and-Repair Pathway of Somatic Hypermutation Genetics, May 1, 2001; 158(1): 369 - 378. [Abstract] [Full Text]

				R. Golub, D. Martin, F. E. Bertrand, M. Cascalho, M. Wabl, and G. E. Wu VH Gene Replacement in Thymocytes J. Immunol., January 15, 2001; 166(2): 855 - 860. [Abstract] [Full Text] [PDF]

				M. Wiesendanger, B. Kneitz, W. Edelmann, and M. D. Scharff Somatic Hypermutation in Muts Homologue (Msh)3-, Msh6-, and Msh3/Msh6-Deficient Mice Reveals a Role for the Msh2-Msh6 Heterodimer in Modulating the Base Substitution Pattern J. Exp. Med., February 7, 2000; 191(3): 579 - 584. [Abstract] [Full Text] [PDF]

				N. Kim, G. Bozek, J. C. Lo, and U. Storb Different Mismatch Repair Deficiencies All Have the Same Effects on Somatic Hypermutation: Intact Primary Mechanism Accompanied by Secondary Modifications J. Exp. Med., July 1, 1999; 190(1): 21 - 30. [Abstract] [Full Text] [PDF]

				U. STORB, A. PETERS, N. KIM, H.M. SHEN, G. BOZEK, N. MICHAEL, J. HACKETT, E. KLOTZ, J.D. REYNOLDS, L.A. LOEB, et al. Molecular Aspects of Somatic Hypermutation of Immunoglobulin Genes Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 227 - 234. [Abstract] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Phung, Q. H. Articles by Gearhart, P. J. Search for Related Content PubMed PubMed Citation Articles by Phung, Q. H. Articles by Gearhart, P. J.