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Title: The role of hypoxia-induced RRM2B in DNA replication
Author: Foskolou, Iosifina Petrina
ISNI:       0000 0004 6496 0158
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Regions of low oxygen (hypoxia) occur in most solid tumours and correlate with poor patient prognosis due to their resistance to chemo- and radiotherapy and to their increased metastatic potential. Severe levels of hypoxia induce DNA replication stress characterised by an increased number of stalled replication forks and significantly reduced replication rates, which occurs in the absence of DNA damage. Ribonucleotide Reductase (RNR) is the only enzyme capable of de novo synthesis of dNTPs - the building blocks of DNA synthesis and repair. However, oxygen is essential for mammalian RNRs (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here we show that the RRM2B subunit of RNR is significantly induced in response to hypoxia in a universal manner. Interestingly, the hypoxic induction of RRM2B occurs both at transcriptional and translational levels and likely through two distinct mechanisms, one of which is p53-dependent. Most importantly, we demonstrate that RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favoured over RRM1/RRM2 in order to preserve on-going replication. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and we identified specific RRM2B-residues (Y164 and K37/K151) responsible for this function. The importance of RRM2B in the response to tumour hypoxia is further illustrated by increased expression in the hypoxic regions of glioblastoma biopsies, roles in tumour growth and radioresistance, as well as prevention of DNA damage and apoptosis. In this study we present multi-disciplinary evidence, demonstrating the molecular rationale for the ability of RRM1/RRM2B to function in hypoxia. We propose that RRM2B has been evolutionary conserved so as to act as the hypoxic specific RNR subunit in order to be able to react promptly when this physiologically relevant stress occurs. Our data provide new insight into RNR biology, highlighting RRM2B as an important, hypoxic-specific, anti-cancer therapeutic target.
Supervisor: Hammond, Ester ; D'Angiolella, Vincenzo Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available