A novel non-canonical forkhead-associated (FHA) domain-binding interface mediates the interaction between Rad53 and Dbf4 proteins

Lindsay A. Matthews, Rajeevan Selvaratnam, Darryl R. Jones, Madoka Akimoto, Brendan J. McConkey, Giuseppe Melacini, Bernard P. Duncker, Alba Guarné

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Forkhead-associated (FHA) and BRCA1 C-terminal (BRCT) domains are overrepresented in DNA damage and replication stress response proteins. They function primarily as phosphoepitope recognition modules but can also mediate non-canonical interactions. The latter are rare, and only a few have been studied atamolecular level. We have identifieda crucial non-canonical interaction between the N-terminal FHA1 domain of the checkpoint effector kinase Rad53 and the BRCT domain of the regulatory subunit of the Dbf4-dependent kinase that is critical to suppress late origin firing and to stabilize stalled forks during replication stress. The Rad53-Dbf4 interaction is phosphorylation-independent and involves a novel non-canonical interface on the FHA1 domain. Mutations within this surface result in hypersensitivity to genotoxic stress. Importantly, this surface is not conservedinthe FHA2 domainof Rad53, suggesting that the FHA domains of Rad53 gain specificity by engaging additional interaction interfaces beyond their phosphoepitope-binding site.Ingeneral, our results point to FHA domains functioning as complex logic gates rather than mere phosphoepitope-targeting modules.

Original languageEnglish
Pages (from-to)2589-2599
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number5
DOIs
Publication statusPublished - 2014 Jan 31

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Matthews, L. A., Selvaratnam, R., Jones, D. R., Akimoto, M., McConkey, B. J., Melacini, G., Duncker, B. P., & Guarné, A. (2014). A novel non-canonical forkhead-associated (FHA) domain-binding interface mediates the interaction between Rad53 and Dbf4 proteins. Journal of Biological Chemistry, 289(5), 2589-2599. https://doi.org/10.1074/jbc.M113.517060