Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells

Br J Cancer. 2017 Jun 27;117(1):113-123. doi: 10.1038/bjc.2017.133. Epub 2017 May 23.


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.

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Blotting, Western
  • CRISPR-Cas Systems
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Line
  • Checkpoint Kinase 1 / antagonists & inhibitors
  • Checkpoint Kinase 2 / antagonists & inhibitors
  • Cisplatin / pharmacology
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • DNA Damage / drug effects
  • DNA Damage / genetics*
  • G2 Phase Cell Cycle Checkpoints
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Minor Histocompatibility Antigens / genetics*
  • Minor Histocompatibility Antigens / metabolism
  • Mutation
  • Nuclear Proteins / antagonists & inhibitors
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • RNA Interference
  • Tumor Suppressor Protein p53 / genetics*
  • Uracil / metabolism


  • Cell Cycle Proteins
  • Minor Histocompatibility Antigens
  • Nuclear Proteins
  • Poly(ADP-ribose) Polymerase Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Uracil
  • Checkpoint Kinase 2
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • APOBEC3B protein, human
  • Cytidine Deaminase
  • Cisplatin