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BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands

DOI: 10.7554/eLife.39979 DOI Help

Authors: Matthew Day (University of Sussex) , Mathieu Rappas (University of Sussex) , Katie Ptasinska (University of Sussex) , Dominik Boos (Universit├Ąt Duisburg-Essen) , Antony W. Oliver (University of Sussex) , Laurence H. Pearl (University of Sussex)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 7

State: Published (Approved)
Published: October 2018

Open Access Open Access

Abstract: TOPBP1 and its fission yeast homologue Rad4, are critical players in a range of DNA replication, repair and damage signalling processes. They are composed of multiple BRCT domains, some of which bind phosphorylated motifs in other proteins. 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. 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. 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. These results provide important insights into how multiple BRCT domains within TOPBP1/Rad4 achieve selective and combinatorial binding of their multiple partner proteins.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography