Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells.
Loading...
Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2017-06-27
Date Accepted
2017-04-24
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.
Citation
British journal of cancer, 2017, 117 (1), pp. 113 - 123
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0007-0920
eISSN
1532-1827
Collections
Research Team
Gene Function