| Title: |
Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer |
| Authors: |
Baker, SC; Mason, AS; Slip, RG; Skinner, KT; Macdonald, A; Masood, O; Harris, RS; Fenton, TR; Periyasamy, M; Ali, S; Southgate, J |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2022 |
| Collection: |
White Rose Research Online (Universities of Leeds, Sheffield & York) |
| Description: |
Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| ISSN: |
0950-9232 |
| Relation: |
https://eprints.whiterose.ac.uk/id/eprint/184256/6/s41388-022-02235-8.pdf; Baker, SC, Mason, AS, Slip, RG et al. (8 more authors) (2022) Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer. Oncogene, 41. pp. 2139-2151. ISSN: 0950-9232 |
| Availability: |
https://eprints.whiterose.ac.uk/id/eprint/184256/ |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.CE0CB64 |
| Database: |
BASE |