BRCT domains of the DNA damage checkpoint proteins TOPBP1/Rad4 display distinct specificities for phosphopeptide ligands.
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Embargo End Date
ICR Authors
Authors
Day, M
Rappas, M
Ptasinska, K
Boos, D
Oliver, AW
Pearl, LH
Rappas, M
Ptasinska, K
Boos, D
Oliver, AW
Pearl, LH
Document Type
Journal Article
Date
2018-10-08
Date Accepted
Abstract
TOPBP1 and its fission yeast homologueRad4, 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.
Citation
ELIFE, 2018, 7
Source Title
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
ISSN
2050-084X