The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity
| Autor: | Giulio Superti-Furga, Thorsten Klampfl, Manuela Gridling, Stefan Kubicek, Branka Radic, Claudia Trefzer, Vincent A. Blomen, Kilian Huber, Robert Kralovics, Cristina Mayor-Ruiz, Georg E. Winter, Thijn R. Brummelkamp, Doris Chen, Oscar Fernandez-Capetillo, Richard Kumaran Kandasamy |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Protein family
DNA repair DNA damage Cell Survival Apoptosis Mice SCID Biology Haploidy Article Mice Genome editing Cell Line Tumor medicine Animals Humans RNA Neoplasm Cloning Molecular Molecular Biology Genome Human Imidazoles Cancer Membrane Transport Proteins Cell Biology medicine.disease Immunohistochemistry Intercalating Agents Solute carrier family Cell biology Comet assay Comet Assay Cell Division Genetic screen DNA Damage Naphthoquinones |
| Popis: | Genotoxic chemotherapy is the most common cancer treatment strategy. However, its untargeted generic DNA-damaging nature and associated systemic cytotoxicity greatly limit its therapeutic applications. Here, we used a haploid genetic screen in human cells to discover an absolute dependency of the clinically evaluated anticancer compound YM155 on solute carrier family member 35 F2 (SLC35F2), an uncharacterized member of the solute carrier protein family that is highly expressed in a variety of human cancers. YM155 generated DNA damage through intercalation, which was contingent on the expression of SLC35F2 and its drug-importing activity. SLC35F2 expression and YM155 sensitivity correlated across a panel of cancer cell lines, and targeted genome editing verified SLC35F2 as the main determinant of YM155-mediated DNA damage toxicity in vitro and in vivo. These findings suggest a new route to targeted DNA damage by exploiting tumor and patient-specific import of YM155. |
| Databáze: | OpenAIRE |
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