Novel Connections Between DNA Replication, Telomere Homeostasis, and the DNA Damage Response Revealed by a Genome-Wide Screen for TEL1/ATM Interactions in Saccharomyces cerevisiae

摘要

[Tel1][1] is the budding yeast ortholog of the mammalian tumor suppressor and DNA damage response (DDR) kinase ATM. However, [tel1][1]-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][1] functions in the DDR nor the mechanism by which [Tel1][1] 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][1]-Δ that cause sensitivity to methyl methanesulfonate (MMS) and/or ionizing radiation, along with follow-up characterizations of the 13 interactions yielded by this screen. Surprisingly, many of the [tel1][1]-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][1]-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][1]-Δ xxx-Δ mutants, we show that depletion of dNTP pools through pretreatment with hydroxyurea renders [tel1][1]-Δ cells (but not wild type) MMS-sensitive, demonstrating that, under certain conditions, [Tel1p][1] does indeed play a critical role in the DDR. [1]: http://www.yeastgenome.org/cgi-bin/locus.fpl?dbid=S000000184