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Set2 methyltransferase facilitates DNA replication and promotes genotoxic stress responses through MBF-dependent transcription

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posted on 2023-06-09, 08:03 authored by Chen-Chun Pai, Anastasiya Kishkevich, Rachel S Deegan, Andrea KeszthelyiAndrea Keszthelyi, Lisa Folkes, Stephen E Kearsey, Nagore De León, Ignacio Soriano, Robertus Antonius Maria de Bruin, Antony CarrAntony Carr, Timothy C Humphrey
Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumour 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 to a checkpoint-dependent S-phase delay. Accordingly, prolonged S-phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Further, 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.

Funding

Single Molecule Imaging of the DNA Damage Response in Live Cells; G0250; EUROPEAN UNION; 268788

History

Publication status

  • Published

File Version

  • Published version

Journal

Cell Reports

ISSN

2211-1247

Publisher

Elsevier

Issue

11

Volume

20

Page range

2693-2705

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-09-22

First Open Access (FOA) Date

2017-09-22

First Compliant Deposit (FCD) Date

2017-09-22

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