Set2 Methyltransferase Facilitates DNA Replication and Promotes Genotoxic Stress Responses through MBF-Dependent Transcription

Publication date: 12 September 2017
Source:Cell Reports, Volume 20, Issue 11
Author(s): Chen-Chun Pai, Anastasiya Kishkevich, Rachel S. Deegan, Andrea Keszthelyi, Lisa Folkes, Stephen E. Kearsey, Nagore De León, Ignacio Soriano, Robertus Antonius Maria de Bruin, Antony M. Carr, Timothy C. Humphrey
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.

Graphical abstract

Teaser

Pai et al. find that the Set2 methyltransferase facilitates dNTP synthesis and DNA replication through promoting MBF-dependent transcription in fission yeast. Set2 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.


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