A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex Journal Article
| Authors: | Dupré, A.; Boyer-Chatenet, L.; Sattler, R. M.; Modi, A. P.; Lee, J. H.; Nicolette, M. L.; Kopelovich, L.; Jasin, M.; Baer, R.; Paull, T. T.; Gautier, J. |
| Article Title: | A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex |
| Abstract: | The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated 6-(4-hydroxyphenyl)-2-thioxo-2,3- dihydro-4(1H)-pyrimidinone (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells. © 2008 Nature Publishing Group. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; dna-binding proteins; nonhuman; dna replication; mammalia; animals; mre11 protein; rad50 protein; cell viability; dna damage; atp-binding cassette transporters; cell cycle; cell cycle progression; complex formation; dna repair; cell line; protein binding; enzyme activity; pyrimidinone derivative; drug design; pyrimidinones; nibrin; dna strand breakage; genomic instability; tumor suppressor proteins; cell cycle g2 phase; cell cycle m phase; molecular structure; exonuclease; genetic screening; radiosensitization; cell extracts; mirin; xenopus laevis; ataxia telangiectasia; chemosensitization; xenopus proteins; 6 (4 hydroxyphenyl) 2 thioxo 2,3 dihydro 4(1h)pyrimidinone; thiones |
| Journal Title: | Nature Chemical Biology |
| Volume: | 4 |
| Issue: | 2 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2008-02-01 |
| Start Page: | 119 |
| End Page: | 125 |
| Language: | English |
| DOI: | 10.1038/nchembio.63 |
| PUBMED: | 18176557 |
| PROVIDER: | scopus |
| PMCID: | PMC3065498 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 42" - "Export Date: 17 November 2011" - "Source: Scopus" |
