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

## TL;DR

A histone modification pathway involving Rtf1 and H2Bub1 helps fission yeast resist multiple drugs, suggesting a shared gene regulation mechanism with RNA polymerase II.

## Contribution

Discovery of a conserved histone modification axis that counteracts drug resistance in fission yeast.

## Key findings

- Mutations in the Rtf1/Prf1-dependent histone modification axis confer resistance to hydroxyurea and azole antifungals in fission yeast.
- Defects in this axis correlate with reduced dNTP pool effects and blunted transcriptional responses to drug treatment.
- Similar drug resistance phenotypes are observed with mutations in the Rpb1 C-terminal repeat domain.

## Abstract

Mutations in a conserved histone modification axis confer a unique drug-tolerant phenotype in fission yeast, and suggest a mode of gene regulation shared with the Rpb1 C-terminal domain.

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 Schizosaccharomyces pombe (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.