RRC ID 59007
著者 Xu YJ, Khan S, Didier AC, Wozniak M, Liu Y, Singh A, Nakamura TM.
タイトル A tel2 Mutation That Destabilizes the Tel2-Tti1-Tti2 Complex Eliminates Rad3ATR Kinase Signaling in the DNA Replication Checkpoint and Leads to Telomere Shortening in Fission Yeast.
ジャーナル Mol Cell Biol
Abstract In response to perturbed DNA replication, ATR (ataxia telangiectasia and Rad3-related) kinase is activated to initiate the checkpoint signaling necessary for maintaining genome integrity and cell survival. To better understand the signaling mechanism, we carried out a large-scale genetic screen in fission yeast looking for mutants with enhanced sensitivity to hydroxyurea. From a collection of ∼370 primary mutants, we found a few mutants in which Rad3 (ATR ortholog)-mediated phospho-signaling was significantly compromised. One such mutant carried an uncharacterized mutation in tel2, a gene encoding an essential and highly conserved eukaryotic protein. Previous studies in various biological models have shown that Tel2 mainly functions in Tel2-Tti1-Tti2 (TTT) complex that regulates the steady-state levels of all phosphatidylinositol 3-kinase-like protein kinases, including ATR. We show here that although the levels of Rad3 and Rad3-mediated phospho-signaling in DNA damage checkpoint were moderately reduced in the tel2 mutant, the phospho-signaling in the DNA replication checkpoint was almost completely eliminated. In addition, the tel2 mutation caused telomere shortening. Since the interactions of Tel2 with Tti1 and Tti2 were significantly weakened by the mutation, destabilization of the TTT complex likely contributes to the observed checkpoint and telomere defects.
巻・号 39(20)
公開日 2019-10-15
DOI 10.1128/MCB.00175-19
PII MCB.00175-19
PMID 31332096
PMC PMC6766693
MeSH Checkpoint Kinase 2 / genetics Checkpoint Kinase 2 / metabolism* DNA Damage / drug effects DNA Replication Hydroxyurea / pharmacology Intracellular Signaling Peptides and Proteins / genetics* Intracellular Signaling Peptides and Proteins / metabolism* Multiprotein Complexes Mutation, Missense Schizosaccharomyces / genetics* Schizosaccharomyces / metabolism Schizosaccharomyces pombe Proteins / genetics* Schizosaccharomyces pombe Proteins / metabolism* Signal Transduction Telomere Shortening* Telomere-Binding Proteins / genetics* Telomere-Binding Proteins / metabolism
IF 3.611
引用数 0
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