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J Cell Sci. 2019 Mar 25;132(6). pii: jcs226969. doi: 10.1242/jcs.226969.

An essential role for dNTP homeostasis following CDK-induced replication stress.

Author information

1
CRUK-MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, UK chen-chun.pai@oncology.ox.ac.uk timothy.humphrey@oncology.ox.ac.uk.
2
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.
3
Department of Surgery, Tri-Service General Hospital, National Defense Medical Centre, Taipei 114, Taiwan.
4
CRUK-MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, ORCRB, Roosevelt Drive, Oxford, OX3 7DQ, UK.
5
Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, Sussex, BN1 9RQ, UK.
6
Department of Zoology, University of Oxford, Zoology Research & Administration Building, Mansfield Road, Oxford, OX1 3PS, UK.
7
Research Department of Genetics, Evolution & Environment, University College London, London, WC1E 6BT, UK.
8
School of Health, Sport and Bioscience, University of East London, Stratford Campus, E15 4LZ, London, UK.

Abstract

Replication stress is a common feature of cancer cells, and thus a potentially important therapeutic target. Here, we show that cyclin-dependent kinase (CDK)-induced replication stress, resulting from Wee1 inactivation, is synthetic lethal with mutations disrupting dNTP homeostasis in fission yeast. Wee1 inactivation leads to increased dNTP demand and replication stress through CDK-induced firing of dormant replication origins. Subsequent dNTP depletion leads to inefficient DNA replication, DNA damage and to genome instability. Cells respond to this replication stress by increasing dNTP supply through histone methyltransferase Set2-dependent MBF-induced expression of Cdc22, the catalytic subunit of ribonucleotide reductase (RNR). Disrupting dNTP synthesis following Wee1 inactivation, through abrogating Set2-dependent H3K36 tri-methylation or DNA integrity checkpoint inactivation results in critically low dNTP levels, replication collapse and cell death, which can be rescued by increasing dNTP levels. These findings support a 'dNTP supply and demand' model in which maintaining dNTP homeostasis is essential to prevent replication catastrophe in response to CDK-induced replication stress.

KEYWORDS:

CDK; Histone H3K36 modification; MBF; Schizosaccharomyces pombe; Set2; Synthetic lethality; Wee1

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