Piening BD, Huang D, Paulovich AG

Tel1 is the budding yeast ortholog of the mammalian tumor suppressor and DNA damage response (DDR) kinase ATM. However, tel1-Δ cells, unlike ATM-deficient cells, do not exhibit sensitivity to DNA damaging agents, but do display shortened (but stably maintained) telomere lengths. Neither the extent to which Tel1p functions in the ...

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DDR nor the mechanism by which Tel1 contributes to telomere metabolism is well-understood. To address the first question, we present the results from a comprehensive genome-wide screen for genetic interactions with tel1-Δ that cause sensitivity to MMS and/or ionizing radiation, along with follow-up characterizations of the 13 interactions yielded by this screen. Surprisingly, many of the tel1-Δ interactions that confer DNA damage sensitivity also exacerbate the short telomere phenotype, suggesting a connection between these two phenomena. Restoration of normal telomere length in the tel1-Δ xxx-Δ mutants results in only minor suppression of the DNA damage sensitivity, demonstrating that the sensitivity of these mutants must also involve mechanisms independent of telomere length. In support of a model for increased replication stress in the tel1-Δ xxx-Δ mutants, we show that depletion of dNTP pools through pre-treatment with hydroxyurea renders tel1-Δ cells (but not wild-type) MMS-sensitive, demonstrating that under certain conditions, Tel1p does indeed play a critical role in the DDR.

Date: Feb. 01, 2013

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