![]() ![]() ![]() However, the structural basis for this specificity has not been defined. Despite the structural similarity of these phosphopeptide-binding BRCT domains, genetic and biochemical studies show that they are nonetheless selective and specific for the phosphopeptide sequences with which they interact ( Leung et al., 2011 Leung et al., 2013 Qu et al., 2013 Rappas et al., 2011 Sun et al., 2017). ![]() In TOPBP1, this is located between BRCT domains 6 and 7, while in the yeast proteins it occurs at the C-terminus, downstream of BRCT4 ( Wardlaw et al., 2014).īioinformatic analysis ( Rappas et al., 2011 Wardlaw et al., 2014) suggests that only three of the BRCT domains in the yeast TOPBP1 homologues, and four in the vertebrate TOPBP1 homologues, possess the required cluster of residues needed to bind phosphorylated peptide motifs. In addition, all members of the family possess a domain required for activation of the DNA damage PI3-kinase-like kinase ATR ( Kumagai et al., 2006 Lin et al., 2012 Mordes et al., 2008a Mordes et al., 2008b2008b). Homologues in vertebrates each contain nine BRCT domains, of which four (at the N-terminus BRCT1,2 and 4,5) are conserved in the yeasts ( Garcia et al., 2005). TOPBP1 and its fission and budding yeast orthologues Rad4 and Dpb11, respectively, are scaffold proteins that mediate formation of multi-protein complexes in a range of essential DNA replication and repair processes ( Wardlaw et al., 2014). The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). These results provide important insights into how multiple BRCT domains within TOPBP1/Rad4 achieve selective and combinatorial binding of their multiple partner proteins.Įditorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. We use this to identify and characterise previously unknown phosphorylation-dependent TOPBP1/Rad4-binding motifs in human RHNO1 and the fission yeast homologue of MDC1, Mdb1. We have now structurally and/or biochemically characterised a sufficient number of high-affinity complexes for the conserved N-terminal region of TOPBP1 and Rad4 with diverse phospho-ligands, including human RAD9 and Treslin, and Schizosaccharomyces pombe Crb2 and Sld3, to define the determinants of BRCT domain specificity. They thus act as multi-point adaptors bringing proteins together into functional combinations, dependent on post-translational modifications downstream of cell cycle and DNA damage signals. They are composed of multiple BRCT domains, some of which bind phosphorylated motifs in other proteins. TOPBP1 and its fission yeast homologue Rad4, are critical players in a range of DNA replication, repair and damage signalling processes. ![]()
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