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

被引：320

作者：

Dupre, Aude ^{[1
]}

Boyer-Chatenet, Louise ^{[1
]}

Sattler, Rose M. ^{[1
]}

Modi, Ami P. ^{[1
]}

Lee, Ji-Hoon ^{[2
,3
]}

Nicolette, Matthew L. ^{[2
,3
]}

Kopelovich, Levy ^{[4
]}

Jasin, Maria ^{[5
]}

Baer, Richard ^{[1
]}

Paull, Tanya T. ^{[2
,3
]}

Gautier, Jean ^{[1
]}

机构：

[1] Columbia Univ, Inst Canc Genet, Irving Canc Res Ctr, New York, NY 10032 USA

[2] Univ Texas Austin, Inst Cell & Mol Biol, Austin, TX 78712 USA

[3] Univ Texas Austin, Dept Mol Genet & Microbiol, Austin, TX 78712 USA

[4] NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA

[5] Mem Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY 10065 USA

来源：

NATURE CHEMICAL BIOLOGY | 2008年 / 4卷 / 02期

关键词：

D O I：

10.1038/nchembio.63

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：119 / 125

页数：7

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