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Nat Chem Biol. 2008 Feb;4(2):119-25. doi: 10.1038/nchembio.63. Epub 2008 Jan 6.

A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex.

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  • 1Columbia University, Institute for Cancer Genetics, Irving Cancer Research Center, 1130 St. Nicholas Avenue, Room 602, New York, New York 10032, USA.

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.

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PMID:
18176557
[PubMed - indexed for MEDLINE]
PMCID:
PMC3065498
Free PMC Article
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