Nucleosomes are comprised of two copies of each of the canonical histones: H2A, H2B, H3, and H4. In Saccharomyces cerevisiae H2A.Z, an H2A variant, replaces canonical histone H2A in about 10% of nucleosomes. Histone H2A.Z has distinct functions from histone H2A and is involved in transcriptional regulation, DNA damage response, and heterochromatin silencing. Rapamycin (sirolimus) is an antifungal drug that inhibits protein synthesis and arrests the cell cycle. Treatment of yeast with rapamycin leads to several phenotypes including cell cycle arrest. Several protein complexes are activated in the presence of rapamycin including the Target Of Rapamycin (TOR) and EGO protein complexes. The protein GTP binding protein Resemblance (GTR1) is a member of the EGO complex. This gene is upregulated in the presence of rapamycin and activates the target of rapamycin complex 1 (TORC1) in response to amino acid stimulation. Loss of GTR1 leads to cellular death in the presence of rapamycin. Here we show that H2A.Z is critical for the proper expression of TOR signal genes, including GTR1. H2A.Z deletion leads to repression of GTR1 in the presence of rapamycin which is the likely reason for intermediate rapamycin sensitivity in the htz1Δ strain. This phenotype is not due to alteration of rapamycin-induced cell cycle arrest. Interestingly, in the htz1Δ/gtr1Δ strain we find rescue of the rapamycin sensitivity phenotype. These data indicate loss of H2A.Z leads to the restoration of an, as yet, unknown rapamycin rescue pathway. Taken together, these data demonstrate a direct genetic interaction between GTR1 and HTZ1.

The activation of the gene GTR1 during rapamycin treatment requires the histone variant H2A.Z in yeast Saccharomyces cerevisiae

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