Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells.
Br J Cancer
; 117(1): 113-123, 2017 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-28535155
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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Regulação Neoplásica da Expressão Gênica
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Antígenos de Histocompatibilidade Menor
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Proteína Supressora de Tumor p53
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Citidina Desaminase
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Pontos de Checagem do Ciclo Celular
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article