Journal
BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 39, Issue -, Pages 600-605Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BST0390600
Keywords
ataxia telangiectasia mutated- and Rad3-related (ATR); cell cycle; checkpoint; DNA damage; DNA replication; Mec1
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Funding
- NIGMS NIH HHS [GM083970, GM032431] Funding Source: Medline
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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 Med. The 9-1-1 clamp functions in checkpoint activation in G(1) - and G(2)-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 G(1)-phase, an activity identified only in S. cerevisiae so far. However, in G(2)-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 Odd. 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 Med.
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