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dc.contributor.authorFoskolou, Iosifina P
dc.contributor.authorJorgensen, Christian
dc.contributor.authorLeszczynska, Katarzyna B
dc.contributor.authorOlcina, Monica M
dc.contributor.authorTarhonskaya, Hanna
dc.contributor.authorHaisma, Bauke
dc.contributor.authorD'Angiolella, Vincenzo
dc.contributor.authorMyers, William K
dc.contributor.authorDomene, Carmen
dc.contributor.authorFlashman, Emily
dc.contributor.authorHammond, Ester M
dc.date.accessioned2020-05-11T23:31:51Z
dc.date.available2020-05-11T23:31:51Z
dc.date.issued2017-04-20
dc.identifier.issn1097-2765
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/305258
dc.description.abstractCells 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectHCT116 Cells
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice, Nude
dc.subjectColonic Neoplasms
dc.subjectDNA Damage
dc.subjectOxygen
dc.subjectRibonucleotide Reductases
dc.subjectRibonucleoside Diphosphate Reductase
dc.subjectCell Cycle Proteins
dc.subjectTumor Suppressor Proteins
dc.subjectDNA, Neoplasm
dc.subjectTumor Burden
dc.subjectXenograft Model Antitumor Assays
dc.subjectTransfection
dc.subjectApoptosis
dc.subjectDNA Replication
dc.subjectRNA Interference
dc.subjectRadiation Tolerance
dc.subjectTime Factors
dc.subjectFemale
dc.subjectTumor Hypoxia
dc.titleRibonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.
dc.typeArticle
prism.endingPage220.e9
prism.issueIdentifier2
prism.publicationDate2017
prism.publicationNameMol Cell
prism.startingPage206
prism.volume66
dc.identifier.doi10.17863/CAM.52345
dcterms.dateAccepted2017-03-07
rioxxterms.versionofrecord10.1016/j.molcel.2017.03.005
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-04-13
dc.contributor.orcidFoskolou, Iosifina [0000-0003-1874-6356]
dc.identifier.eissn1097-4164
rioxxterms.typeJournal Article/Review
cam.issuedOnline2017-04-13


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International