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

Day, Matthew, Rappas, Mathieu, Ptasinska, Katie, Boos, Dominik, Oliver, Antony W and Pearl, Laurence H (2018) BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands. eLife, 7 (e39979). pp. 1-18. ISSN 2050-084X

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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 phosphorylationdependent 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > Q Science (General)
Depositing User: Antony Oliver
Date Deposited: 09 Oct 2018 14:18
Last Modified: 02 Jul 2019 14:19
URI: http://sro.sussex.ac.uk/id/eprint/79292

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Project NameSussex Project NumberFunderFunder Ref
Structural Biology of DNA Damage Response and Repair MechanismsG2176CANCER RESEARCH UKC302/A24386
Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug DiscovG0891CANCER RESEARCH UKUnset