Two types of drug synergy, genetic and promiscuous, are explored in S. cerevisiae. The results suggest that promiscuous synergy predominates, and that propensity to synergize is an intrinsic drug property with the potential to accelerate the search for synergistic drug combinations.
ONE SENTENCE SUMMARY: MET-2/SETDB1 and interactors LIN-65/ATF7IP and ARLE-14/ARL14EP initiate heterochromatin formation during embryogenesis.
ABSTRACTHeterochromatin formation during early embryogenesis is timed precisely, but it has been elusive how this process is regulated. Here we report the discovery of a histone methyltransferase complex whose nuclear accumulation and activation establishes the onset of heterochromatin formation in C. elegans embryos. We find that the inception of heterochromatin generation coincides with the accumulation of the Histone H3 Lysine 9 (H3K9) methyltransferase MET-2 (SETDB) into nuclear hubs. The absence of MET-2 results in delayed and disturbed heterochromatin formation, whereas accelerated nuclear localization of the methyltransferase leads to precocious H3K9 methylation. We identify two factors that bind to and function with MET-2: LIN-65, which resembles ATF7IP, localizes MET-2 into nuclear hubs, and ARLE-14, orthologous to ARL14EP, promotes stable association of MET-2 with chromatin. These data reveal that nuclear accumulation of MET-2 in conjunction with LIN-65 and ARLE-14 regulates timing of heterochromatin domains during embryogenesis.
SUMMARY
One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound (“drug”) pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate.
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