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dc.contributor.authorKanu, N
dc.contributor.authorCerone, MA
dc.contributor.authorGoh, G
dc.contributor.authorZalmas, L-P
dc.contributor.authorBartkova, J
dc.contributor.authorDietzen, M
dc.contributor.authorMcGranahan, N
dc.contributor.authorRogers, R
dc.contributor.authorLaw, EK
dc.contributor.authorGromova, I
dc.contributor.authorKschischo, M
dc.contributor.authorWalton, MI
dc.contributor.authorRossanese, OW
dc.contributor.authorBartek, J
dc.contributor.authorHarris, RS
dc.contributor.authorVenkatesan, S
dc.contributor.authorSwanton, C
dc.date.accessioned2020-06-15T10:51:18Z
dc.date.issued2016-09-15
dc.identifier.citationGenome biology, 2016, 17 (1), pp. 185 - ?
dc.identifier.issn1474-7596
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3738
dc.identifier.eissn1474-760X
dc.identifier.doi10.1186/s13059-016-1042-9
dc.description.abstractBACKGROUND: The APOBEC3 family of cytidine deaminases mutate the cancer genome in a range of cancer types. Although many studies have documented the downstream effects of APOBEC3 activity through next-generation sequencing, less is known about their upstream regulation. In this study, we sought to identify a molecular basis for APOBEC3 expression and activation. RESULTS: HER2 amplification and PTEN loss promote DNA replication stress and APOBEC3B activity in vitro and correlate with APOBEC3 mutagenesis in vivo. HER2-enriched breast carcinomas display evidence of elevated levels of replication stress-associated DNA damage in vivo. Chemical and cytotoxic induction of replication stress, through aphidicolin, gemcitabine, camptothecin or hydroxyurea exposure, activates transcription of APOBEC3B via an ATR/Chk1-dependent pathway in vitro. APOBEC3B activation can be attenuated through repression of oncogenic signalling, small molecule inhibition of receptor tyrosine kinase signalling and alleviation of replication stress through nucleoside supplementation. CONCLUSION: These data link oncogene, loss of tumour suppressor gene and drug-induced replication stress with APOBEC3B activity, providing new insights into how cytidine deaminase-induced mutagenesis might be activated in tumourigenesis and limited therapeutically.
dc.formatElectronic
dc.format.extent185 - ?
dc.languageeng
dc.language.isoeng
dc.publisherBMC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectCell Transformation, Neoplastic
dc.subjectDNA Damage
dc.subjectCytidine Deaminase
dc.subjectCytosine Deaminase
dc.subjectAntineoplastic Agents
dc.subjectSignal Transduction
dc.subjectDNA Replication
dc.subjectGene Amplification
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectMutagenesis
dc.subjectEnzyme Activation
dc.subjectMutation
dc.subjectMultigene Family
dc.subjectOncogenes
dc.subjectFemale
dc.subjectStress, Physiological
dc.subjectGene Knockdown Techniques
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.subjectBiomarkers, Tumor
dc.titleDNA replication stress mediates APOBEC3 family mutagenesis in breast cancer.
dc.typeJournal Article
dcterms.dateAccepted2016-08-09
rioxxterms.versionofrecord10.1186/s13059-016-1042-9
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-09-15
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfGenome biology
pubs.issue1
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Target Evaluation and Molecular Therapeutics
pubs.publication-statusPublished
pubs.volume17
pubs.embargo.termsNot known
icr.researchteamSignal Transduction & Molecular Pharmacology
icr.researchteamTarget Evaluation and Molecular Therapeutics
dc.contributor.icrauthorRogers, Rebecca
dc.contributor.icrauthorRossanese, Olivia


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