Pharmacology Research Today is a free monthly online journal that collates and summarizes the latest research about Pharmacology, including details on pharmacogenomics, drug development, new medications.

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

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

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.

Published 18 January 2008 in Nat Chem Biol, 4(2): 119-25.
Full-text of this article is available online (may require subscription).

© 2005-2008 Pharmacology Research Today. All Rights Reserved.