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Mol Cell. 2017 Apr 20;66(2):206-220.e9. doi: 10.1016/j.molcel.2017.03.005. Epub 2017 Apr 13.

Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.

Author information

1
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
2
Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK.
3
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
4
Inorganic Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QR, UK.
5
Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
6
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: ester.hammond@oncology.ox.ac.uk.

Abstract

Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target.

KEYWORDS:

DNA damage response; P53; RNR; RRM2B; hypoxia; nucleotides; radiosensitivity; replication stress

PMID:
28416140
PMCID:
PMC5405111
DOI:
10.1016/j.molcel.2017.03.005
[Indexed for MEDLINE]
Free PMC Article

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