Unknown

Dataset Information

0

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


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.

SUBMITTER: Dupre A 

PROVIDER: S-EPMC3065498 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Dupré Aude A   Boyer-Chatenet Louise L   Sattler Rose M RM   Modi Ami P AP   Lee Ji-Hoon JH   Nicolette Matthew L ML   Kopelovich Levy L   Jasin Maria M   Baer Richard R   Paull Tanya T TT   Gautier Jean J  

Nature chemical biology 20080106 2


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 r  ...[more]

Similar Datasets

| S-EPMC2801237 | biostudies-literature
| S-EPMC2675615 | biostudies-literature
| S-EPMC5609712 | biostudies-literature
| S-EPMC7407228 | biostudies-literature
| S-EPMC8593132 | biostudies-literature
| S-EPMC4525285 | biostudies-literature
| S-EPMC2315671 | biostudies-literature
| S-EPMC6443204 | biostudies-literature
| S-EPMC2811014 | biostudies-literature
| S-EPMC2868538 | biostudies-literature