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.

1. Columbia University, Institute for Cancer Genetics, Irving Cancer Research Center, 1130 St. Nicholas Avenue, Room 602, New York, New York 10032, USA.
2. Department of Molecular Genetics and Microbiology and the Institute of Cellular and Molecular Biology, University of Texas, 1 University Station, A4800, Austin, Texas 78712, USA.
3. Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., MSC 7315, Bethesda, Maryland 20892, USA.
4. Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, 430 East 67^th Street, New York, New York 10065, USA.
5. Present addresses: Centre National de la Recherche Scientifique-Unité Mixte de recherche 7622, case 24, 4 place Jussieu 75005 Paris, France (A.D.) and Service de cardiologie, 184, rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France (L.B.-C.).
6. These authors contributed equally to this work.

Correspondence to: Jean Gautier¹ e-mail: jg130@columbia.edu

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