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Mol Cell. 2013 Sep 26;51(6):723-36. doi: 10.1016/j.molcel.2013.08.030.

Phosphorylation-dependent assembly and coordination of the DNA damage checkpoint apparatus by Rad4(TopBP¹).

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  • 1National Institute of Biological Sciences, 7 Science Park Road, ZGC Life Science Park, Beijing 102206, China.

Abstract

The BRCT-domain protein Rad4(TopBP1) facilitates activation of the DNA damage checkpoint in Schizosaccharomyces pombe by physically coupling the Rad9-Rad1-Hus1 clamp, the Rad3(ATR) -Rad26(ATRIP) kinase complex, and the Crb2(53BP1) mediator. We have now determined crystal structures of the BRCT repeats of Rad4(TopBP1), revealing a distinctive domain architecture, and characterized their phosphorylation-dependent interactions with Rad9 and Crb2(53BP1). We identify a cluster of phosphorylation sites in the N-terminal region of Crb2(53BP1) that mediate interaction with Rad4(TopBP1) and reveal a hierarchical phosphorylation mechanism in which phosphorylation of Crb2(53BP1) residues Thr215 and Thr235 promotes phosphorylation of the noncanonical Thr187 site by scaffolding cyclin-dependent kinase (CDK) recruitment. Finally, we show that the simultaneous interaction of a single Rad4(TopBP1) molecule with both Thr187 phosphorylation sites in a Crb2(53BP1) dimer is essential for establishing the DNA damage checkpoint.

Copyright © 2013 Elsevier Inc. All rights reserved.

PMID:
24074952
[PubMed - indexed for MEDLINE]
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