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A Mutation That Destabilizes the Tel2-Tti1-Tti2 Complex Eliminates Rad3 Kinase Signaling in the DNA Replication Checkpoint and Leads to Telomere Shortening in Fission Yeast. | LitMetric

AI Article Synopsis

  • ATR kinase is activated to maintain genome integrity and cell survival during DNA replication issues, and a genetic screen in fission yeast identified mutants sensitive to hydroxyurea.
  • Among the mutants, one had a mutation in a gene related to a crucial protein that affects Rad3 (ATR ortholog) phospho-signaling, revealing a significant compromise in DNA replication checkpoint signaling.
  • The mutation weakened interactions in the Tel2-Tti1-Tti2 complex, leading to reduced Rad3 signaling, telomere shortening, and defects in both DNA damage and replication checkpoints.

Article 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 , 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 mutant, the phospho-signaling in the DNA replication checkpoint was almost completely eliminated. In addition, the 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766693PMC
http://dx.doi.org/10.1128/MCB.00175-19DOI Listing

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