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Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast.

Original publication




Journal article


Cell Rep

Publication Date





2693 - 2705


DNA replication, MBF, Schizosaccharomyces pombe, Set2, dNTP, histone H3K36 methylation, histone methylation, ribonucleotide reductase, Cell Cycle Checkpoints, Cell Cycle Proteins, DNA Damage, DNA Replication, DNA, Fungal, Down-Regulation, Gene Expression Regulation, Fungal, Genes, Fungal, Histone-Lysine N-Methyltransferase, Mutation, Nucleotides, Replication Origin, S Phase, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Transcription Factors, Transcription, Genetic