Structural highlights
Function
[RAD4_SCHPO] Essential component for DNA replication and also the checkpoint control system which couples S and M phases. May directly or indirectly interact with chromatin proteins to form the complex required for the initiation and/or progression of DNA synthesis. [RHP9_SCHPO] Essential for cell cycle arrest at the G1 and G2 stages following DNA damage by X-, and UV-irradiation, or inactivation of DNA ligase. Plays a role in the response to DNA damage.[1] [2] [3]
Publication Abstract from PubMed
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.
Phosphorylation-Dependent Assembly and Coordination of the DNA Damage Checkpoint Apparatus by Rad4(TopBP1.).,Qu M, Rappas M, Wardlaw CP, Garcia V, Ren JY, Day M, Carr AM, Oliver AW, Du LL, Pearl LH Mol Cell. 2013 Sep 26;51(6):723-36. doi: 10.1016/j.molcel.2013.08.030. PMID:24074952[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Willson J, Wilson S, Warr N, Watts FZ. Isolation and characterization of the Schizosaccharomyces pombe rhp9 gene: a gene required for the DNA damage checkpoint but not the replication checkpoint. Nucleic Acids Res. 1997 Jun 1;25(11):2138-46. PMID:9153313
- ↑ Saka Y, Esashi F, Matsusaka T, Mochida S, Yanagida M. Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1. Genes Dev. 1997 Dec 15;11(24):3387-400. PMID:9407031
- ↑ Sanders SL, Portoso M, Mata J, Bahler J, Allshire RC, Kouzarides T. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell. 2004 Nov 24;119(5):603-14. PMID:15550243 doi:http://dx.doi.org/10.1016/j.cell.2004.11.009
- ↑ Qu M, Rappas M, Wardlaw CP, Garcia V, Ren JY, Day M, Carr AM, Oliver AW, Du LL, Pearl LH. Phosphorylation-Dependent Assembly and Coordination of the DNA Damage Checkpoint Apparatus by Rad4(TopBP1.). Mol Cell. 2013 Sep 26;51(6):723-36. doi: 10.1016/j.molcel.2013.08.030. PMID:24074952 doi:http://dx.doi.org/10.1016/j.molcel.2013.08.030
