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Nat Chem Biol
2008 Feb 01;42:119-25. doi: 10.1038/nchembio.63.
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A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex.
Dupré A
,
Boyer-Chatenet L
,
Sattler RM
,
Modi AP
,
Lee JH
,
Nicolette ML
,
Kopelovich L
,
Jasin M
,
Baer R
,
Paull TT
,
Gautier J
.
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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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