| Literature DB >> 24074952 |
Meng Qu1, Mathieu Rappas2, Christopher P Wardlaw3, Valerie Garcia3, Jing-Yi Ren1, Matthew Day2, Antony M Carr3, Antony W Oliver2, Li-Lin Du1, Laurence H Pearl2.
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.Entities:
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Year: 2013 PMID： 24074952 PMCID： PMC4944838 DOI： 10.1016/j.molcel.2013.08.030
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970