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.
PubMed ID: 18176557
PMC ID: PMC3065498
Article link: Nat Chem Biol.
Grant support: CA92245 NCI NIH HHS , CA95866 NCI NIH HHS , CA97403 NCI NIH HHS , GM54668 NIGMS NIH HHS , R01 CA092245-06 NCI NIH HHS , R01 GM054668-11 NIGMS NIH HHS , P01 CA097403 NCI NIH HHS , R01 CA092245 NCI NIH HHS , R01 GM054668 NIGMS NIH HHS
Genes referenced: atm mre11a nbn rad50