Abstract
SummaryChromatin 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.
Highlights
DNA replication is a highly regulated process, and its fidelity plays a primary role in maintaining genome stability (Aguilera and Gomez-Gonzalez, 2008)
These factors facilitate the Cdt1-dependent loading of the mini-chromosome maintenance (MCM) complex, and subsequently multiple additional replication factors associate with the replication origin following activation of cyclin-dependent kinase (CDK) and
Efficient and accurate DNA replication elongation requires a balanced supply of deoxyribonucleoside triphosphates, generated in eukaryotes through the reduction of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates, which is catalyzed by ribonucleotide reductase (RNR)
Summary
Deegan, ..., Robertus Antonius Maria de Bruin, Antony M. Pai et al find that the Set methyltransferase facilitates dNTP synthesis and DNA replication through promoting MBF-dependent transcription in fission yeast. Set loss results in reduced ribonucleotide reductase expression, reduced dNTP synthesis, altered replication origin firing, and checkpoint-dependent S-phase delay. These findings suggest how H3K36 methylation suppresses replication stress. 2017, Cell Reports 20, 2693–2705 September 12, 2017 a 2017 The Authors.
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