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An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis

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An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis [CANCER RESEARCH 64, 517–522, January 15, 2004] An Msh2 Point Mutation Uncouples DNA Mismatch Repair and Apoptosis Diana P. Lin,1 Yuxun Wang,1 Stefan J. Scherer,1 Alan B. Clark,2 Kan Yang,3 Elena Avdievich,1 Bo Jin,1 Uwe Werling,1 Tchaiko Parris,1 Naoto Kurihara,3 Asad Umar,2 Raju Kucherlapati,4 Martin Lipkin,3 Thomas A. Kunkel,2 and Winfried Edelmann1 1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York; 2Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Department of Health and Human Services, Research Triangle Park, North Carolina; 3Strang Cancer Research Laboratory at The Rockefeller University, New York, New York; and 4Harvard-Partners Center for Genetics and Genomics, Boston, Massachusetts ABSTRACT These studies were performed with MMR-deficient cell lines that com- pletely lack particular MMR proteins and therefore lack all of the func- Mutations in the human DNA mismatch repair gene MSH2 are associated tions of those proteins. However, a significant proportion of HNPCC with hereditary nonpolyposis colorectal cancer as well as a significant pro- patients carry missense mutations in MMR genes (1), and it is unclear portion of sporadic colorectal cancer. The inactivation of MSH2 results in the accumulation of somatic mutations in the genome of tumor cells and resist- how these mutations affect individual MMR protein functions in DNA ance to the genotoxic effects of a variety of chemotherapeutic agents. Here we repair and damage responses. G674A show that the DNA repair and DNA damage-induced apoptosis functions of We therefore decided to generate a mouse line carrying the Msh2 Msh2 can be uncoupled using mice that carry the G674A missense mutation missense mutation to assess its impact on MMR and response to DNA in the conserved ATPase domain. As a consequence, although Msh2G674A damage and examine the consequences with respect to cancer suscepti- homozygous mutant mice are highly tumor prone, the onset of tumorigenesis bility. The mutation results in a glycine to alanine change at amino acid is delayed as compared with Msh2-null mice. In addition, tumors that carry residue 674 within the conserved ATPase domain at the COOH-terminal the mutant allele remain responsive to treatment with a chemotherapeutic region. This domain is characterized by the Walker “type A” motif agent. Our results indicate that Msh2-mediated apoptosis is an important GXXXXGKS/T (G denotes the modified G674 amino acid residue) component of tumor suppression and that certain MSH2 missense mutations known to coordinate the phosphate groups of ATP in many proteins that can cause mismatch repair deficiency while retaining the signaling functions that confer sensitivity to chemotherapeutic agents. hydrolyze ATP (18–20). Mutations in this MutS domain in bacteria and yeast result in MMR defects, and overexpression of these mutant proteins was shown to cause dominant mutator phenotypes (21–24). The impor- INTRODUCTION tance of ATP processing for MMR and tumorigenesis is underscored by the significant number of HNPCC missense mutations that are located in The DNA mismatch repair (MMR) system guards against genomic the ATP-binding domains of MSH2 (25). instability, and mutations in the human MMR genes MutS homolog 2 Here we show that the Msh2G674A mutation has differential effects (MSH2) and MutL homolog 1 (MLH1) are the cause of the majority of on the DNA repair and DNA damage response functions. Whereas it hereditary nonpolyposis colorectal cancer [HNPCC (1)]. Recent studies caused DNA repair deficiency that resulted in a strong cancer predis- indicate that MMR proteins not only protect mammalian genomes by position phenotype in the mice, it did not affect the DNA damage repairing mismatched bases that result from erroneous DNA replication, response function of Msh2. As a consequence, tumorigenesis in but also by mediating DNA damage-induced apoptosis as part of the Ϫ Ϫ Msh2G674A/G674A mice was delayed as compared with that in Msh2 / cellular response to endogenous and exogenous agents (2–4). These Ϫ Ϫ mice. In addition, unlike Msh2 / cells, Msh2G674A/G674A mouse studies showed that cell lines derived from HNPCC and MMR-defective embryonic fibroblasts (MEFs) and teratocarcinomas remained sensi- sporadic tumors or MMR-deficient mice displayed increased mutation tive to treatment with genotoxic agents. rates in their genomes and also had increased resistance to the genotoxic effects of a variety of DNA damage-inducing agents, including cisplatin, temozolomide and N-methyl-NЈ-nitro-N-nitrosoguanidine [MNNG MATERIALS AND METHODS (5–10)]. In addition, as demonstrated initially in yeast and later in mam- Generation of Msh2G674A Mice. A 3.6-kb HincII fragment containing Msh2 malian cells, MMR has been implicated in the removal of endogenous exon 13 was isolated from a 129SvEv bacterial artificial chromosome genomic lesions such as mutagenic 8-oxoguanine that is incorporated from the library and subcloned. A mutation was introduced that changed codon 674 from oxidized deoxynucleotide triphosphate pool during DNA replication (11, glycine (GGT) to alanine (GCT) by site-directed mutagenesis (Stratagene Quick 12). It has been suggested that the failure to clear DNA damage-bearing Change Kit). A 5.0-kb NotI fragment containing two LoxP sites flanking a cells may be responsible in part for the increased mutation frequency in neomycin-PGKhygromycin resistance cassette was subcloned into the single SpeI MMR mutant cells and also may confer a selective advantage in tumor site. The modified HincII fragment was subsequently used to modify the Msh2 cells (13–16). This hypothesis is consistent with the observation that genomic locus in bacterial artificial chromosome clone mB183k13 of the RPCI-22 MMR deficiency in mouse tissues leads to an elevation in mutation 129 mouse genomic library by RecET-mediated recombination (26). A 24-kb frequency after the mice are exposed to DNA-damaging agents (10, 17). KpnI fragment containing the modified locus was excised from the bacterial artificial chromosome clone and used for gene targeting in WW6 embryonic stem (ES) cells (27). Three correctly targeted ES cell lines were injected into C57BL/6J Received 9/18/03; revised 10/20/03; accepted 11/5/03. blastocysts. Male chimeras from all three lines were mated to C57BL/6J females Grant support: NIH Grants CA76329 and CA93484 (to W. E.), CA84301 and ES11040 (to R. K.), CN05117 (to M. L.) and Center Grant CA13330 (to the Albert and transmitted the mutant allele through their germ line. Subsequently, F1 males Einstein College of Medicine); a Deutsche Krebshilfe fellowship (to S. J. S.); and an Irma carrying the mutant allele were mated to Zp3Cre transgenic females (C57BL/6J) T. Hirschl Career Scientist Award (to W. E.). to remove the resistance cassette by LoxP-mediated recombination. Male and The costs of publication of this article were defrayed in part by the payment of page female mice carrying the modified allele were intercrossed to generate Msh2ϩ/ϩ, charges. This article must therefore be hereby marked advertisement in accordance with G674A/ϩ G674A/G674A 18 U.S.C. Section 1734 solely to indicate this fact. Msh2 , and Msh2 mutant mice. Notes: D. P. Lin, Y. Wang, and S. J. Scherer contributed equally to this work. Reverse Transcription-PCR Analysis. Total RNA was isolated from Msh2 Supplementary data for this article are available at Cancer Research Online (http:// mutant ES cell lines using Trizol (GibcoBRL). Reverse transcription-PCR was cancerres.aacrjournals.org). performed with forward primer 5Ј-CGTAGAGCCAATGCAGACGCT-3Ј and Requests for reprints: Winfried Edelmann, Department of Cell Biology, Albert Ј Ј Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. reverse primer 5 -GGATGGAAGAAGTCTCCAGC-3 using the one Tube re- Phone: (718) 430-2030; Fax: (718) 430-8574; E-mail: [email protected]. verse transcription-PCR reaction kit (Roche) according to the manufacturer’s 517 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2004 American Association for Cancer Research. DNA REPAIR AND DAMAGE-INDUCED APOPTOSIS IN MUTANT MICE instructions. The following cycling conditions were used: 30 min at 50°C(1 RESULTS cycle); 2 min at 94°C,30sat60°C, and 45 s at 68°C (35 cycles); and 7 min at 68°C G674A (1 cycle). The resulting 280-bp fragment was digested with either MnlI to detect Generation of Msh2 Mutant Mice. The mutant mouse line the wild-type RNA transcript or AluI to detect the mutant RNA transcript. was created by a knockin gene targeting strategy (Fig. 1A). Analysis of 22 G674A Western Blot Analysis. MEF cell extracts were prepared according to stand- litters of the F2 offspring showed that the Msh2 allele was trans- ϩ ϩ ϩ ard procedures, and 50 ␮g of protein of each cell lysate were separated on a 10% mitted in a normal Mendelian ratio with 40 Msh2 / ,89Msh2G674A/ , SDS-PAGE gel. Protein was transferred onto a PROTRAN membrane, and the and 37 Msh2G674A/G674A. None of the heterozygous or homozygous membranes were subsequently incubated with mouse monoclonal antibodies di- animals displayed any developmental abnormalities. Molecular analysis rected against Msh2 (Ab-2; Oncogene), Msh6 (clone 44; BD Biosciences), and showed that the Msh2G674A mutation allowed normal gene expression ␤-actin (C-2; Santa Cruz Biotechnology). and did not interfere with the stability of the mutant protein (Fig. 1, C and Gel Mobility Shift Assays. Nuclear extracts were prepared as described D). In eukaryotes,
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