dc.contributor.author | Kanu, N | |
dc.contributor.author | Cerone, MA | |
dc.contributor.author | Goh, G | |
dc.contributor.author | Zalmas, L-P | |
dc.contributor.author | Bartkova, J | |
dc.contributor.author | Dietzen, M | |
dc.contributor.author | McGranahan, N | |
dc.contributor.author | Rogers, R | |
dc.contributor.author | Law, EK | |
dc.contributor.author | Gromova, I | |
dc.contributor.author | Kschischo, M | |
dc.contributor.author | Walton, MI | |
dc.contributor.author | Rossanese, OW | |
dc.contributor.author | Bartek, J | |
dc.contributor.author | Harris, RS | |
dc.contributor.author | Venkatesan, S | |
dc.contributor.author | Swanton, C | |
dc.date.accessioned | 2020-06-15T10:51:18Z | |
dc.date.issued | 2016-09-15 | |
dc.identifier.citation | Genome biology, 2016, 17 (1), pp. 185 - ? | |
dc.identifier.issn | 1474-7596 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3738 | |
dc.identifier.eissn | 1474-760X | |
dc.identifier.doi | 10.1186/s13059-016-1042-9 | |
dc.description.abstract | BACKGROUND: 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.format | Electronic | |
dc.format.extent | 185 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BMC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | Cell Transformation, Neoplastic | |
dc.subject | DNA Damage | |
dc.subject | Cytidine Deaminase | |
dc.subject | Cytosine Deaminase | |
dc.subject | Antineoplastic Agents | |
dc.subject | Signal Transduction | |
dc.subject | DNA Replication | |
dc.subject | Gene Amplification | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Mutagenesis | |
dc.subject | Enzyme Activation | |
dc.subject | Mutation | |
dc.subject | Multigene Family | |
dc.subject | Oncogenes | |
dc.subject | Female | |
dc.subject | Stress, Physiological | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | Ataxia Telangiectasia Mutated Proteins | |
dc.subject | Biomarkers, Tumor | |
dc.title | DNA replication stress mediates APOBEC3 family mutagenesis in breast cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-08-09 | |
rioxxterms.versionofrecord | 10.1186/s13059-016-1042-9 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-09-15 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Genome biology | |
pubs.issue | 1 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 17 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Target Evaluation and Molecular Therapeutics | |
dc.contributor.icrauthor | Rogers, Rebecca | |
dc.contributor.icrauthor | Rossanese, Olivia | |