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Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Blank, Jonathan L. Liu, Xiaozhen J. Cosmopoulos, Katherine Louise Panagiota Bouck, David C. Garcia, Khristofer Bernard, Hugues Tayber, Olga Hather, Greg Liu, Ray Narayanan, Usha Milhollen, Michael A. Lightcap, Eric S. |
| Copyright Year | 2013 |
| Abstract | MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription-coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G(2)-M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S-G(2) phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924. |
| Starting Page | 174109 |
| Ending Page | 174109 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/73/1/225.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2012/10/23/0008-5472.CAN-12-1729.full.pdf |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/early/2012/12/24/0008-5472.CAN-12-1729.full.pdf |
| PubMed reference number | 23100467v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-12-1729 |
| DOI | 10.1158/0008-5472.can-12-1729 |
| Journal | Cancer research |
| Volume Number | 73 |
| Issue Number | 1 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Angiotensin-Converting Enzyme Inhibitors Base Excision Repair Blast Phase Cell Cycle Checkpoints Cell Death Cessation of life Colon Carcinoma DNA Damage DNA Replication Flow Cytometry Leukemia, B-Cell Ligase MLN4924 NEDD8 Activating Enzyme Ubiquitination investigational monitoring program transcription-coupled nucleotide-excision repair |
| Content Type | Text |
| Resource Type | Article |
