Cell-cycle-specific activators of the Mec1/ATR checkpoint kinase

Vasundhara M. Navadgi-Patil, Peter M. Burgers

Research output: Contribution to journalReview articlepeer-review

24 Scopus citations

Abstract

Mec1 [ATR (ataxia telangiectasia mutated- and Rad3-related) in humans] is the principle kinase responsible for checkpoint activation in response to replication stress and DNA damage in Saccharomyces cerevisiae. The heterotrimeric checkpoint clamp, 9-1-1 (checkpoint clamp of Rad9, Rad1 and Hus1 in humans and Ddc1, Rad17 and Mec3 in S. cerevisiae; Ddc1-Mec3-Rad17) and the DNA replication initiation factor Dpb11 (human TopBP1) are the two known activators of Mec1. The 9-1-1 clamp functions in checkpoint activation in G 1- and G2 -phase, but its employment differs between these two phases of the cell cycle. The Ddc1 (human Rad9) subunit of the clamp directly activates Mec1 in G1-phase, an activity identified only in S. cerevisiae so far. However, in G2-phase, the 9-1-1 clamp activates the checkpoint by two mechanisms. One mechanism includes direct activation of Mec1 by the unstructured C-terminal tail of Ddc1. The second mechanism involves the recruitment of Dpb11 by the phosphorylated C-terminal tail of Ddc1. The latter mechanism is highly conserved and also functions in response to replication stress in higher eukaryotes. In S. cerevisiae, however, both the 9-1-1 clamp and the Dpb11 are partially redundant for checkpoint activation in response to replication stress, suggesting the existence of additional activators of Mec1.

Original languageEnglish
Pages (from-to)600-605
Number of pages6
JournalBiochemical Society transactions
Volume39
Issue number2
DOIs
StatePublished - Apr 2011

Keywords

  • Ataxia telangiectasia mutated- and Rad3-related (ATR)
  • Cell cycle
  • Checkpoint
  • DNA damage
  • DNA replication
  • Mec1

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