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

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posted on 2023-06-09, 15:25 authored by Matthew Day, Mathieu Rappas, Katie Ptasinska, Dominik Boos, Antony OliverAntony Oliver, Laurence PearlLaurence Pearl
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.

Funding

Structural Biology of DNA Damage Response and Repair Mechanisms and its Exploitation for Drug Discov; G0891; CANCER RESEARCH UK

Structural Biology of DNA Damage Response and Repair Mechanisms; G2176; CANCER RESEARCH UK; C302/A24386

History

Publication status

  • Published

File Version

  • Published version

Journal

eLife

ISSN

2050-084X

Publisher

eLife Sciences Publications

Issue

e39979

Volume

7

Page range

1-18

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-10-09

First Open Access (FOA) Date

2018-10-09

First Compliant Deposit (FCD) Date

2018-10-09

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