Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.
Mol Cell
; 66(2): 206-220.e9, 2017 Apr 20.
Article
in En
| MEDLINE
| ID: mdl-28416140
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxygen
/
Ribonucleotide Reductases
/
DNA, Neoplasm
/
Colonic Neoplasms
/
Cell Cycle Proteins
/
Tumor Suppressor Proteins
/
DNA Replication
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Mol Cell
Journal subject:
BIOLOGIA MOLECULAR
Year:
2017
Document type:
Article
Affiliation country: