The Rtf1/Prf1-dependent histone modification axis counteracts multi-drug resistance in fission yeast

RNA polymerase II transcription elongation directs an intricate pattern of histone modifications. This pattern includes a regulatory cascade initiated by the elongation factor Rtf1, leading to monoubiquitylation of histone H2B, and subsequent methylation of histone H3 on lysine 4. Previous studies h...

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Bibliographic Details
Published in:Life science alliance 2024-06, Vol.7 (6), p.e202302494
Main Authors: Chen, Jennifer J, Moy, Calvin, Pagé, Viviane, Monnin, Cian, El-Hajj, Ziad W, Avizonis, Daina Z, Reyes-Lamothe, Rodrigo, Tanny, Jason C
Format: Article
Language:English
Subjects:
Drug Resistance, Multiple
Histone Code
Histones - genetics
Histones - metabolism
RNA Polymerase II - genetics
RNA Polymerase II - metabolism
Schizosaccharomyces - genetics
Schizosaccharomyces - metabolism
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Summary:RNA polymerase II transcription elongation directs an intricate pattern of histone modifications. This pattern includes a regulatory cascade initiated by the elongation factor Rtf1, leading to monoubiquitylation of histone H2B, and subsequent methylation of histone H3 on lysine 4. Previous studies have defined the molecular basis for these regulatory relationships, but it remains unclear how they regulate gene expression. To address this question, we investigated a drug resistance phenotype that characterizes defects in this axis in the model eukaryote (fission yeast). The mutations caused resistance to the ribonucleotide reductase inhibitor hydroxyurea (HU) that correlated with a reduced effect of HU on dNTP pools, reduced requirement for the S-phase checkpoint, and blunting of the transcriptional response to HU treatment. Mutations in the C-terminal repeat domain of the RNA polymerase II large subunit Rpb1 led to similar phenotypes. Moreover, all the HU-resistant mutants also exhibited resistance to several azole-class antifungal agents. Our results suggest a novel, shared gene regulatory function of the Rtf1-H2Bub1-H3K4me axis and the Rpb1 C-terminal repeat domain in controlling fungal drug tolerance.
ISSN:2575-1077
2575-1077
DOI:10.26508/lsa.202302494