Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells.
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Date
2017-06-27Author
Nikkilä, J
Kumar, R
Campbell, J
Brandsma, I
Pemberton, HN
Wallberg, F
Nagy, K
Scheer, I
Vertessy, BG
Serebrenik, AA
Monni, V
Harris, RS
Pettitt, SJ
Ashworth, A
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cell Line
Humans
DNA Damage
Cisplatin
Uracil
Cytidine Deaminase
Cell Cycle Proteins
Nuclear Proteins
Minor Histocompatibility Antigens
Blotting, Western
Gene Expression Regulation, Neoplastic
RNA Interference
Mutation
Tumor Suppressor Protein p53
Protein-Tyrosine Kinases
Gene Knockout Techniques
HEK293 Cells
Cell Cycle Checkpoints
G2 Phase Cell Cycle Checkpoints
Ataxia Telangiectasia Mutated Proteins
Checkpoint Kinase 2
CRISPR-Cas Systems
Poly(ADP-ribose) Polymerase Inhibitors
Checkpoint Kinase 1
Research team
Gene Function
Language
eng
Date accepted
2017-04-24
License start date
2017-06
Citation
British journal of cancer, 2017, 117 (1), pp. 113 - 123
Publisher
NATURE PUBLISHING GROUP
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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