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

Jenni Nikkilä, Rahul Kumar, James Campbell, Inger Brandsma, Helen N. Pemberton, Fredrik Wallberg, Kinga Nagy, Ildikó Scheer, B. Vértessy, Artur A. Serebrenik, Valentina Monni, Reuben S. Harris, Stephen J. Pettitt, Alan Ashworth, Christopher J. Lord

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)113-123
Number of pages11
JournalBritish Journal of Cancer
Volume117
Issue number1
DOIs
Publication statusPublished - Jun 27 2017

Fingerprint

DNA Damage
Mutation
Uracil
Biomarkers
Cell Cycle Checkpoints
Phenotype
Neoplasms
Therapeutics
RNA Interference
Cisplatin
Hypersensitivity
Genome
Enzymes
Poly(ADP-ribose) Polymerase Inhibitors

Keywords

  • APOBEC3B
  • cell cycle
  • DNA damage
  • drug sensitivity
  • mutation signature

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. / Nikkilä, Jenni; Kumar, Rahul; Campbell, James; Brandsma, Inger; Pemberton, Helen N.; Wallberg, Fredrik; Nagy, Kinga; Scheer, Ildikó; Vértessy, B.; Serebrenik, Artur A.; Monni, Valentina; Harris, Reuben S.; Pettitt, Stephen J.; Ashworth, Alan; Lord, Christopher J.

In: British Journal of Cancer, Vol. 117, No. 1, 27.06.2017, p. 113-123.

Research output: Contribution to journalArticle

Nikkilä, J, Kumar, R, Campbell, J, Brandsma, I, Pemberton, HN, Wallberg, F, Nagy, K, Scheer, I, Vértessy, B, Serebrenik, AA, Monni, V, Harris, RS, Pettitt, SJ, Ashworth, A & Lord, CJ 2017, 'Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells', British Journal of Cancer, vol. 117, no. 1, pp. 113-123. https://doi.org/10.1038/bjc.2017.133
Nikkilä, Jenni ; Kumar, Rahul ; Campbell, James ; Brandsma, Inger ; Pemberton, Helen N. ; Wallberg, Fredrik ; Nagy, Kinga ; Scheer, Ildikó ; Vértessy, B. ; Serebrenik, Artur A. ; Monni, Valentina ; Harris, Reuben S. ; Pettitt, Stephen J. ; Ashworth, Alan ; Lord, Christopher J. / Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells. In: British Journal of Cancer. 2017 ; Vol. 117, No. 1. pp. 113-123.
@article{abe4b91f49664a6bb7c5bb416b10acde,
title = "Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells",
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.",
keywords = "APOBEC3B, cell cycle, DNA damage, drug sensitivity, mutation signature",
author = "Jenni Nikkil{\"a} and Rahul Kumar and James Campbell and Inger Brandsma and Pemberton, {Helen N.} and Fredrik Wallberg and Kinga Nagy and Ildik{\'o} Scheer and B. V{\'e}rtessy and Serebrenik, {Artur A.} and Valentina Monni and Harris, {Reuben S.} and Pettitt, {Stephen J.} and Alan Ashworth and Lord, {Christopher J.}",
year = "2017",
month = "6",
day = "27",
doi = "10.1038/bjc.2017.133",
language = "English",
volume = "117",
pages = "113--123",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells

AU - Nikkilä, Jenni

AU - Kumar, Rahul

AU - Campbell, James

AU - Brandsma, Inger

AU - Pemberton, Helen N.

AU - Wallberg, Fredrik

AU - Nagy, Kinga

AU - Scheer, Ildikó

AU - Vértessy, B.

AU - Serebrenik, Artur A.

AU - Monni, Valentina

AU - Harris, Reuben S.

AU - Pettitt, Stephen J.

AU - Ashworth, Alan

AU - Lord, Christopher J.

PY - 2017/6/27

Y1 - 2017/6/27

N2 - 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.

AB - 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.

KW - APOBEC3B

KW - cell cycle

KW - DNA damage

KW - drug sensitivity

KW - mutation signature

UR - http://www.scopus.com/inward/record.url?scp=85021432459&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021432459&partnerID=8YFLogxK

U2 - 10.1038/bjc.2017.133

DO - 10.1038/bjc.2017.133

M3 - Article

C2 - 28535155

AN - SCOPUS:85021432459

VL - 117

SP - 113

EP - 123

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 1

ER -