Jenni Nikkilä 1 , Rahul Kumar 1 , James Campbell 1 , Inger Brandsma 1 , Helen N Pemberton 1 , Fredrik Wallberg 2 , Kinga Nagy 3 , 4 , Ildikó Scheer 3 , 4 , Beata G Vertessy 3 , Artur A Serebrenik 5 , Valentina Monni 5 , Reuben S Harris 5 , Stephen J Pettitt 1 , Alan Ashworth 1 , * , Christopher J Lord 1 , *
23 May 2017
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.
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.
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.