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MBC in Press, published online ahead of print September 27, 2006
Mol. Biol. Cell 10.1091/mbc.E06-05-0469

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Submitted on May 31, 2006
Revised on September 5, 2006
Accepted on September 18, 2006

TIF1 Activates the Intra-S Phase Checkpoint Response in the Diploid Micronucleus and Amitotic Polyploid Macronucleus of Tetrahymena

J. Sebastian Yakisich,* Pamela Y. Sandoval,* Tara L. Morrison, and Geoffrey M. Kapler

Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843-1114

Monitoring Editor: Orna Cohen-Fix

The ribosomal DNA origin binding protein, Tif1p, regulates the timing of rDNA replication and is required globally for proper S phase progression and division of the Tetrahymena thermophila macronucleus. Here we show that Tif1p safeguards chromosomes from DNA damage in the mitotic micronucleus and amitotic macronucleus. TIF1p localization is dynamically regulated, as it moves into the microand macronucleus during the respective S phases. TIF1 disruption mutants are hypersensitive to hydroxyurea and methylmethanesulphonate, inducers of DNA damage and intraS phase checkpoint arrest in all examined eukaryotes. TIF1 mutants incur double-strand breaks in the absence of exogenous genotoxic stress, destabilizing all five micronuclear chromosomes. Wild type Tetrahymena elicits an intraS phase checkpoint response that is induced by hydroxyurea and suppressed by caffeine, an inhibitor of the apical checkpoint kinase, ATR/MEC1. In contrast, hydroxyurea-challenged TIF1 mutants fail to arrest in S phase or exhibit caffeine-sensitive Rad51 overexpression, indicating the involvement of TIF1 in checkpoint activation. Although aberrant microand macronuclear division occurs in TIF1 mutants and caffeine-treated wild type cells, TIF1p bears no similarity to ATR or its substrates. We propose that TIF1 and ATR function in the same epistatic pathway to regulate checkpoint responses in the diploid mitotic micronucleus and polyploid amitotic macronucleus.

*These authors contributed equally to this work.

Address correspondence to: Geoffrey M. Kapler (gkapler{at}tamu.edu)




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Tetrahymena POT1a Regulates Telomere Length and Prevents Activation of a Cell Cycle Checkpoint
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[Abstract] [Full Text] [PDF]


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