A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication
Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression libra...
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| Veröffentlicht in: | Somatic cell and molecular genetics 1999-01, Vol.25 (1), p.9-26 |
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| container_title | Somatic cell and molecular genetics |
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| creator | Levenson, V V Lausch, E Kirschling, D J Broude, E V Davidovich, I A Libants, S Fedosova, V Roninson, I B |
| description | Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence. |
| doi_str_mv | 10.1023/b:scam.0000007136.49230.b3 |
| format | Article |
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To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. 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To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.</description><subject>Antineoplastic Agents - pharmacology</subject><subject>aphidicolin</subject><subject>Aphidicolin - pharmacology</subject><subject>Base Sequence</subject><subject>DNA Replication - drug effects</subject><subject>DNA, Antisense - genetics</subject><subject>DNA, Complementary - genetics</subject><subject>DNA, Complementary - isolation & purification</subject><subject>doxorubicin</subject><subject>Doxorubicin - pharmacology</subject><subject>Drug Resistance - genetics</subject><subject>Gene Library</subject><subject>Genes, Suppressor</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>hydroxyurea</subject><subject>Hydroxyurea - pharmacology</subject><subject>Molecular Sequence Data</subject><subject>Tumor Cells, Cultured</subject><issn>0740-7750</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT1PwzAQhj2AaCn8BWQxsCXYseMk3UL5lAoMwGz541yM8kWcDPx7QlsJNm654Z73vdO9CJ1TElOSsEu9DEbVMdlWRpmIeZEwEmt2gOYk4yTKspTM0HEIHxOR5yw9QjNKiiTNCJkjW2LT1to3avBtg1uHN9DA4A0OY9f1EELbY6ighmYIuOtbOxoIeBr4MKjGAB5abPtxE7Bv3r32g282-PqpnJCu8mZre4IOnaoCnO77Ar3d3ryu7qP1893DqlxHhnExRAmlmXBWaatBp4KTzFmeJ7rQHBJrrBWQOKqcYAaAUiAmmYRAuc2dEtyxBbrY-U53fo4QBln7YKCqVAPtGKQoeEEpJf-CNEtTUYh0Apc70PRtCD042fW-Vv2XpET-BCCv5MuqfJS_AchtAFKzSXy23zLqGuwf6e777Bso24fG</recordid><startdate>19990101</startdate><enddate>19990101</enddate><creator>Levenson, V V</creator><creator>Lausch, E</creator><creator>Kirschling, D J</creator><creator>Broude, E V</creator><creator>Davidovich, I A</creator><creator>Libants, S</creator><creator>Fedosova, V</creator><creator>Roninson, I B</creator><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>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19990101</creationdate><title>A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication</title><author>Levenson, V V ; Lausch, E ; Kirschling, D J ; Broude, E V ; Davidovich, I A ; Libants, S ; Fedosova, V ; Roninson, I B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c346t-21176fdabdbeb56407fd482b9b4e2dcdd6e2f1af63cee11e0c2c34e14d8fa64f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Antineoplastic Agents - pharmacology</topic><topic>aphidicolin</topic><topic>Aphidicolin - pharmacology</topic><topic>Base Sequence</topic><topic>DNA Replication - drug effects</topic><topic>DNA, Antisense - genetics</topic><topic>DNA, Complementary - genetics</topic><topic>DNA, Complementary - isolation & purification</topic><topic>doxorubicin</topic><topic>Doxorubicin - pharmacology</topic><topic>Drug Resistance - genetics</topic><topic>Gene Library</topic><topic>Genes, Suppressor</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>hydroxyurea</topic><topic>Hydroxyurea - pharmacology</topic><topic>Molecular Sequence Data</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Levenson, V V</creatorcontrib><creatorcontrib>Lausch, E</creatorcontrib><creatorcontrib>Kirschling, D J</creatorcontrib><creatorcontrib>Broude, E V</creatorcontrib><creatorcontrib>Davidovich, I A</creatorcontrib><creatorcontrib>Libants, S</creatorcontrib><creatorcontrib>Fedosova, V</creatorcontrib><creatorcontrib>Roninson, I B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Somatic cell and molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Levenson, V V</au><au>Lausch, E</au><au>Kirschling, D J</au><au>Broude, E V</au><au>Davidovich, I A</au><au>Libants, S</au><au>Fedosova, V</au><au>Roninson, I B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication</atitle><jtitle>Somatic cell and molecular genetics</jtitle><addtitle>Somat Cell Mol Genet</addtitle><date>1999-01-01</date><risdate>1999</risdate><volume>25</volume><issue>1</issue><spage>9</spage><epage>26</epage><pages>9-26</pages><issn>0740-7750</issn><abstract>Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.</abstract><cop>United States</cop><pmid>10925700</pmid><doi>10.1023/b:scam.0000007136.49230.b3</doi><tpages>18</tpages></addata></record> |
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| subjects | Antineoplastic Agents - pharmacology aphidicolin Aphidicolin - pharmacology Base Sequence DNA Replication - drug effects DNA, Antisense - genetics DNA, Complementary - genetics DNA, Complementary - isolation & purification doxorubicin Doxorubicin - pharmacology Drug Resistance - genetics Gene Library Genes, Suppressor HeLa Cells Humans hydroxyurea Hydroxyurea - pharmacology Molecular Sequence Data Tumor Cells, Cultured |
| title | A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication |
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