Inhibition of the Nedd8 System Sensitizes Cells to DNA Interstrand Cross-linking Agents
- 1 March 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 10 (3), 369-377
- https://doi.org/10.1158/1541-7786.mcr-11-0497
Abstract
The Fanconi anemia pathway is required for repair of DNA interstrand cross-links (ICL). Fanconi anemia pathway–deficient cells are hypersensitive to DNA ICL–inducing drugs such as cisplatin. Conversely, hyperactivation of the Fanconi anemia pathway is a mechanism that may underlie cellular resistance to DNA ICL agents. Modulating FANCD2 monoubiquitination, a key step in the Fanconi anemia pathway, may be an effective therapeutic approach to conferring cellular sensitivity to ICL agents. Here, we show that inhibition of the Nedd8 conjugation system increases cellular sensitivity to DNA ICL–inducing agents. Mechanistically, the Nedd8 inhibition, either by siRNA-mediated knockdown of Nedd8-conjugating enzymes or treatment with a Nedd8-activating enzyme inhibitor MLN4924, suppressed DNA damage–induced FANCD2 monoubiquitination and CHK1 phosphorylation. Our data indicate that inhibition of the Fanconi anemia pathway is largely responsible for the heightened cellular sensitivity to DNA ICLs upon Nedd8 inhibition. These results suggest that a combination of Nedd8 inhibition with ICL-inducing agents may be an effective strategy for sensitizing a subset of drug-resistant cancer cells. Mol Cancer Res; 10(3); 369–77. ©2012 AACR.Keywords
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This publication has 38 references indexed in Scilit:
- Inhibition of NEDD8-Activating Enzyme Induces Rereplication and Apoptosis in Human Tumor Cells Consistent with Deregulating CDT1 TurnoverCancer Research, 2011
- NEDD8-Targeting Drug MLN4924 Elicits DNA Rereplication by Stabilizing Cdt1 in S Phase, Triggering Checkpoint Activation, Apoptosis, and Senescence in Cancer CellsCancer Research, 2010
- Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility geneNature Genetics, 2010
- Cdk1 Participates in BRCA1-Dependent S Phase Checkpoint Control in Response to DNA DamageMolecular Cell, 2009
- An inhibitor of NEDD8-activating enzyme as a new approach to treat cancerNature, 2009
- E2-RING Expansion of the NEDD8 Cascade Confers Specificity to Cullin ModificationMolecular Cell, 2009
- A novel cell‐free screen identifies a potent inhibitor of the Fanconi anemia pathwayInternational Journal of Cancer, 2008
- DNA repair pathways as targets for cancer therapyNature Reviews Cancer, 2008
- FANCF methylation contributes to chemoselectivity in ovarian cancerCancer Cell, 2003
- Disruption of the Fanconi anemia–BRCA pathway in cisplatin-sensitive ovarian tumorsNature Medicine, 2003