Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 publication

DOI

10.1016/j.molcel.2017.03.005

Type

Journal article

Journal

Mol Cell

Publication Date

20/04/2017

Volume

66

Pages

206 - 220.e9

Keywords

DNA damage response, P53, RNR, RRM2B, hypoxia, nucleotides, radiosensitivity, replication stress, Animals, Apoptosis, Cell Cycle Proteins, Colonic Neoplasms, DNA Damage, DNA Replication, DNA, Neoplasm, Female, HCT116 Cells, Humans, Mice, Inbred BALB C, Mice, Nude, Oxygen, RNA Interference, Radiation Tolerance, Ribonucleoside Diphosphate Reductase, Ribonucleotide Reductases, Time Factors, Transfection, Tumor Burden, Tumor Hypoxia, Tumor Suppressor Proteins, Xenograft Model Antitumor Assays