Two-stage mechanism for activation of the DNA replication checkpoint kinase Cds1 in fission yeast

Yong Jie Xu, Matthew Davenport, Thomas J. Kelly

Research output: Contribution to journalArticlepeer-review

Abstract

The DNA replication checkpoint is a complex signal transduction pathway, present in all eukaryotic cells, that functions to maintain genomic integrity and cell viability when DNA replication is perturbed. In Schizosaccharomyces pombe the major effector of the replication checkpoint is the protein kinase Cds1. Activation of Cds1 is known to require the upstream kinase Rad3 and the mediator Mrc1, but the biochemical mechanism of activation is not well understood. We report that the replication checkpoint is activated in two stages. In the first stage, Mrc1 recruits Cds1 to stalled replication forks by interactions between the FHA domain of Cds1 and specific phosphorylated Rad3 consensus sites in Mrc1. Cds1 is then primed for activation by Rad3-dependent phosphorylation. In the second stage, primed Cds1 molecules dimerize via phospho-specific interactions mediated by the FHA domains and are activated by autophosphorylation. This two-stage activation mechanism for the replication checkpoint allows for rapid activation with a high signal-to-noise ratio.

Original languageEnglish (US)
Pages (from-to)990-1003
Number of pages14
JournalGenes and Development
Volume20
Issue number8
DOIs
StatePublished - Apr 15 2006
Externally publishedYes

Keywords

  • Cds1 autoactivation
  • Cds1 autophosphorylation
  • Cds1 dimerization
  • Mrc1 SQ cluster
  • Mrc1 TQ repeats
  • Replication checkpoint

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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