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


Type
Article
Change log
Authors
Foskolou, Iosifina P 
Jorgensen, Christian 
Leszczynska, Katarzyna B 
Olcina, Monica M 
Tarhonskaya, Hanna 
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.

Description
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
Journal Title
Mol Cell
Conference Name
Journal ISSN
1097-2765
1097-4164
Volume Title
66
Publisher
Elsevier BV