dc.contributor.author | Nikkilä, J | |
dc.contributor.author | Kumar, R | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Brandsma, I | |
dc.contributor.author | Pemberton, HN | |
dc.contributor.author | Wallberg, F | |
dc.contributor.author | Nagy, K | |
dc.contributor.author | Scheer, I | |
dc.contributor.author | Vertessy, BG | |
dc.contributor.author | Serebrenik, AA | |
dc.contributor.author | Monni, V | |
dc.contributor.author | Harris, RS | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2017-10-17T09:15:17Z | |
dc.date.issued | 2017-06-27 | |
dc.identifier.citation | British journal of cancer, 2017, 117 (1), pp. 113 - 123 | |
dc.identifier.issn | 0007-0920 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/850 | |
dc.identifier.eissn | 1532-1827 | |
dc.identifier.doi | 10.1038/bjc.2017.133 | |
dc.description.abstract | BACKGROUND: Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on these phenotypes using an isogenic system. METHODS: We used RNA interference of p53 in cells with inducible APOBEC3B and assessed DNA damage response (DDR) biomarkers. The mutational effects of APOBEC3B were assessed using whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was used to identify candidate therapeutic vulnerabilities. RESULTS: Although APOBEC3B expression increased the incorporation of genomic uracil, invoked DDR biomarkers and caused cell cycle arrest, inactivation of p53 circumvented APOBEC3B-induced cell cycle arrest without reversing the increase in genomic uracil or DDR biomarkers. The continued expression of APOBEC3B in p53-defective cells not only caused a kataegic mutational signature but also caused hypersensitivity to small-molecule DDR inhibitors (ATR, CHEK1, CHEK2, PARP, WEE1 inhibitors) as well as cisplatin/ATR inhibitor and ATR/PARP inhibitor combinations. CONCLUSIONS: Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells. | |
dc.format | Print-Electronic | |
dc.format.extent | 113 - 123 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PUBLISHING GROUP | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line | |
dc.subject | Humans | |
dc.subject | DNA Damage | |
dc.subject | Cisplatin | |
dc.subject | Uracil | |
dc.subject | Cytidine Deaminase | |
dc.subject | Cell Cycle Proteins | |
dc.subject | Nuclear Proteins | |
dc.subject | Minor Histocompatibility Antigens | |
dc.subject | Blotting, Western | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | RNA Interference | |
dc.subject | Mutation | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.subject | Protein-Tyrosine Kinases | |
dc.subject | Gene Knockout Techniques | |
dc.subject | HEK293 Cells | |
dc.subject | Cell Cycle Checkpoints | |
dc.subject | G2 Phase Cell Cycle Checkpoints | |
dc.subject | Ataxia Telangiectasia Mutated Proteins | |
dc.subject | Checkpoint Kinase 2 | |
dc.subject | CRISPR-Cas Systems | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Checkpoint Kinase 1 | |
dc.title | Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-04-24 | |
rioxxterms.versionofrecord | 10.1038/bjc.2017.133 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc-sa/4.0 | |
rioxxterms.licenseref.startdate | 2017-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | British journal of cancer | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
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/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 117 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Lord, Christopher | |