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DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair
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| Zeitschriftentitel: | Clinical Cancer Research |
|---|---|
| Personen und Körperschaften: | , , , |
| In: | Clinical Cancer Research, 12, 2006, 2, S. 563-568 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. |
|---|---|
| author |
Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. |
| spellingShingle |
Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. Clinical Cancer Research DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair Cancer Research Oncology |
| author_sort |
lin, xinjian |
| spelling |
Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-05-1380 <jats:title>Abstract</jats:title> <jats:p>The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase ζ, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol ζ by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol ζ-dependent translesional bypass. The HCT116+ch3 (MMR+/REV3+) and HCT116 (MMR−/REV3+) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR−/REV3+ cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol ζ plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR−/REV3+ cells to express a gene burdened by DDP adducts are all dependent on the Pol ζ pathway.</jats:p> DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair Clinical Cancer Research |
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10.1158/1078-0432.ccr-05-1380 |
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American Association for Cancer Research (AACR), 2006 |
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American Association for Cancer Research (AACR), 2006 |
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1078-0432 1557-3265 |
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| title |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_unstemmed |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_full |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_fullStr |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_full_unstemmed |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_short |
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_sort |
dna polymerase ζ accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost dna mismatch repair |
| topic |
Cancer Research Oncology |
| url |
http://dx.doi.org/10.1158/1078-0432.ccr-05-1380 |
| publishDate |
2006 |
| physical |
563-568 |
| description |
<jats:title>Abstract</jats:title>
<jats:p>The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase ζ, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol ζ by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol ζ-dependent translesional bypass. The HCT116+ch3 (MMR+/REV3+) and HCT116 (MMR−/REV3+) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR−/REV3+ cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol ζ plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR−/REV3+ cells to express a gene burdened by DDP adducts are all dependent on the Pol ζ pathway.</jats:p> |
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| author | Lin, Xinjian, Trang, Julie, Okuda, Tsuyoshi, Howell, Stephen B. |
| author_facet | Lin, Xinjian, Trang, Julie, Okuda, Tsuyoshi, Howell, Stephen B., Lin, Xinjian, Trang, Julie, Okuda, Tsuyoshi, Howell, Stephen B. |
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| description | <jats:title>Abstract</jats:title> <jats:p>The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase ζ, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol ζ by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol ζ-dependent translesional bypass. The HCT116+ch3 (MMR+/REV3+) and HCT116 (MMR−/REV3+) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR−/REV3+ cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol ζ plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR−/REV3+ cells to express a gene burdened by DDP adducts are all dependent on the Pol ζ pathway.</jats:p> |
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| imprint_str_mv | American Association for Cancer Research (AACR), 2006 |
| institution | DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229, DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161 |
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| spelling | Lin, Xinjian Trang, Julie Okuda, Tsuyoshi Howell, Stephen B. 1078-0432 1557-3265 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1078-0432.ccr-05-1380 <jats:title>Abstract</jats:title> <jats:p>The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase ζ, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol ζ by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol ζ-dependent translesional bypass. The HCT116+ch3 (MMR+/REV3+) and HCT116 (MMR−/REV3+) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR−/REV3+ cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol ζ plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR−/REV3+ cells to express a gene burdened by DDP adducts are all dependent on the Pol ζ pathway.</jats:p> DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair Clinical Cancer Research |
| spellingShingle | Lin, Xinjian, Trang, Julie, Okuda, Tsuyoshi, Howell, Stephen B., Clinical Cancer Research, DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair, Cancer Research, Oncology |
| title | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_full | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_fullStr | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_full_unstemmed | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_short | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| title_sort | dna polymerase ζ accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost dna mismatch repair |
| title_unstemmed | DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1078-0432.ccr-05-1380 |