Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication

Iosifina P. Foskolou, Christian Jorgensen, Katarzyna B. Leszczynska, Monica M. Olcina, Hanna Tarhonskaya, Bauke Haisma, Vincenzo D’Angiolella, William K. Myers, Carmen Domene, Emily Flashman, Ester M. Hammond

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)206-220
JournalMOLECULAR CELL
Volume66
Issue number2
Early online date13 Apr 2017
DOIs
Publication statusPublished - 13 Apr 2017

Keywords

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

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