Separation of Killing and Tumorigenic Effects of an Alkylating Agent in Mice Defective in two of the DNA Repair Genes
Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyl...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1998-04, Vol.95 (9), p.5116-5120 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Kawate, Hisaya Sakumi, Kunihiko Tsuzuki, Teruhisa Nakatsuru, Yoko Ishikawa, Takatoshi Takahashi, Seiichi Takano, Hiroshi Noda, Tetsuo Sekiguchi, Mutsuo |
| description | Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/-MLH1+/+mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/-MLH1-/-mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways. |
| doi_str_mv | 10.1073/pnas.95.9.5116 |
| format | Article |
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The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/-MLH1+/+mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/-MLH1-/-mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.95.9.5116</identifier><identifier>PMID: 9560238</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Adaptor Proteins, Signal Transducing ; Alkylating Agents - toxicity ; Alleles ; Animals ; Biological Sciences ; Bone marrow ; Carrier Proteins ; Cell lines ; Cellular biology ; Deoxyribonucleic acid ; DNA ; DNA mismatch repair ; DNA Repair ; Enzymes ; Exons ; Female ; Genetic mutation ; Genetics ; Lymphoma ; Lymphoma - chemically induced ; Lymphoma - pathology ; Male ; Methylnitrosourea ; Mice ; Mice, Knockout ; MutL Protein Homolog 1 ; Neoplasm Proteins - genetics ; Neoplasm Proteins - physiology ; Neoplasms, Experimental - chemically induced ; Neoplasms, Experimental - genetics ; Neoplasms, Experimental - pathology ; Nuclear Proteins ; O-Methylguanine-DNA Methyltransferase - physiology ; Rodents ; Survival Analysis ; Thymus Neoplasms - chemically induced ; Thymus Neoplasms - pathology ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1998-04, Vol.95 (9), p.5116-5120</ispartof><rights>Copyright 1993-1998 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Apr 28, 1998</rights><rights>Copyright © 1998, The National Academy of Sciences 1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-c62876649aa60cb9773ab61824458df97c2a75f1fb01666a79167c043b123a793</citedby><cites>FETCH-LOGICAL-c579t-c62876649aa60cb9773ab61824458df97c2a75f1fb01666a79167c043b123a793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/95/9.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/44676$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/44676$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,724,777,781,800,882,27905,27906,53772,53774,57998,58231</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9560238$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kawate, Hisaya</creatorcontrib><creatorcontrib>Sakumi, Kunihiko</creatorcontrib><creatorcontrib>Tsuzuki, Teruhisa</creatorcontrib><creatorcontrib>Nakatsuru, Yoko</creatorcontrib><creatorcontrib>Ishikawa, Takatoshi</creatorcontrib><creatorcontrib>Takahashi, Seiichi</creatorcontrib><creatorcontrib>Takano, Hiroshi</creatorcontrib><creatorcontrib>Noda, Tetsuo</creatorcontrib><creatorcontrib>Sekiguchi, Mutsuo</creatorcontrib><title>Separation of Killing and Tumorigenic Effects of an Alkylating Agent in Mice Defective in two of the DNA Repair Genes</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/-MLH1+/+mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/-MLH1-/-mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Alkylating Agents - toxicity</subject><subject>Alleles</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Bone marrow</subject><subject>Carrier Proteins</subject><subject>Cell lines</subject><subject>Cellular biology</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA mismatch repair</subject><subject>DNA Repair</subject><subject>Enzymes</subject><subject>Exons</subject><subject>Female</subject><subject>Genetic mutation</subject><subject>Genetics</subject><subject>Lymphoma</subject><subject>Lymphoma - chemically induced</subject><subject>Lymphoma - pathology</subject><subject>Male</subject><subject>Methylnitrosourea</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>MutL Protein Homolog 1</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - physiology</subject><subject>Neoplasms, Experimental - chemically induced</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Nuclear Proteins</subject><subject>O-Methylguanine-DNA Methyltransferase - physiology</subject><subject>Rodents</subject><subject>Survival Analysis</subject><subject>Thymus Neoplasms - chemically induced</subject><subject>Thymus Neoplasms - pathology</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1vFCEYxonR1LV69WBiQjz0NiNfA0PiZVNrNVZNtJ4JyzJbVhZWYPrx38tkN9vqwROB5_e8PG8eAF5i1GIk6Ntt0LmVXSvbDmP-CMwwkrjhTKLHYIYQEU3PCHsKnuW8RgjJrkdH4Eh2HBHaz8D4w2510sXFAOMAPzvvXVhBHZbwctzE5FY2OAPPhsGakidEBzj3v-589VRwXvUCXYBfnLHwvZ0wd22nl3ITJ75c1fevc_i9fuQSPLfB5ufgyaB9ti_25zH4-eHs8vRjc_Ht_NPp_KIxnZClMZz0gtddtObILKQQVC847gljXb8cpDBEi27AwwJhzrkWEnNhEKMLTGi90WPwbjd3Oy42dmlq1qS92ia30elORe3U30pwV2oVrxVBhNBqP9nbU_w92lzUxmVjvdfBxjErzCnruWQVfPMPuI5jCnW1OglTLrggFWp3kEkx52SHQw6M1NSlmrpUslNSTV1Ww-uH6Q_4vrwH-uS7V-_9J__T1TB6X-xtqeCrHbjOJaYDyVgNTv8AtWu6jQ</recordid><startdate>19980428</startdate><enddate>19980428</enddate><creator>Kawate, Hisaya</creator><creator>Sakumi, Kunihiko</creator><creator>Tsuzuki, Teruhisa</creator><creator>Nakatsuru, Yoko</creator><creator>Ishikawa, Takatoshi</creator><creator>Takahashi, Seiichi</creator><creator>Takano, Hiroshi</creator><creator>Noda, Tetsuo</creator><creator>Sekiguchi, Mutsuo</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>19980428</creationdate><title>Separation of Killing and Tumorigenic Effects of an Alkylating Agent in Mice Defective in two of the DNA Repair Genes</title><author>Kawate, Hisaya ; 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The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/-MLH1+/+mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/-MLH1-/-mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9560238</pmid><doi>10.1073/pnas.95.9.5116</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1998-04, Vol.95 (9), p.5116-5120 |
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| source | MEDLINE; Jstor Complete Legacy; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Adaptor Proteins, Signal Transducing Alkylating Agents - toxicity Alleles Animals Biological Sciences Bone marrow Carrier Proteins Cell lines Cellular biology Deoxyribonucleic acid DNA DNA mismatch repair DNA Repair Enzymes Exons Female Genetic mutation Genetics Lymphoma Lymphoma - chemically induced Lymphoma - pathology Male Methylnitrosourea Mice Mice, Knockout MutL Protein Homolog 1 Neoplasm Proteins - genetics Neoplasm Proteins - physiology Neoplasms, Experimental - chemically induced Neoplasms, Experimental - genetics Neoplasms, Experimental - pathology Nuclear Proteins O-Methylguanine-DNA Methyltransferase - physiology Rodents Survival Analysis Thymus Neoplasms - chemically induced Thymus Neoplasms - pathology Tumors |
| title | Separation of Killing and Tumorigenic Effects of an Alkylating Agent in Mice Defective in two of the DNA Repair Genes |
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