TopBP1 activates the ATR-ATRIP complex

被引：597

作者：

Kumagai, A ^{[1
]}

Lee, J ^{[1
]}

Yoo, HY ^{[1
]}

Dunphy, WG ^{[1
]}

机构：

[1] CALTECH, Div Biol 21 76, Pasadena, CA 91125 USA

来源：

CELL | 2006年 / 124卷 / 05期

关键词：

D O I：

10.1016/j.cell.2005.12.041

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：

ATR is a key regulator of checkpoint responses to incompletely replicated and damaged DNA, but the mechanisms underlying control of its kinase activity are unknown. TopBP1, the vertebrate homolog of yeast Cut5/Dbp11, has dual roles in initiation of DNA replication and regulation of checkpoint responses. We show that recombinant TopBP1 induces a large increase in the kinase activity of both Xenopus and human ATR. The ATR-activating domain resides in a conserved segment of TopBP1 that is distinct from its numerous BRCT repeats. The isolated ATR-activating domain from TopBP1 induces ectopic activation of ATR-dependent signaling in both Xenopus egg extracts and human cells. Furthermore, Xenopus egg extracts containing a version of TopBP1 with an inactivating point mutation in the ATR-activating domain are defective in checkpoint regulation. These studies establish that activation of ATR by TopBP1 is a crucial step in the initiation of ATR-dependent signaling processes.

引用

页码：943 / 955

页数：13

共 53 条

[1] Cell cycle checkpoint signaling through the ATM and ATR kinases [J].