Imperial College London
Alternate

ProfessorSimakAli

Faculty of Medicine, Department of Surgery & Cancer

Professor of Molecular Endocrine Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2811simak.ali

 
 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Baker:2022:10.1038/s41388-022-02235-8,
author = {Baker, SC and Mason, AS and Slip, RG and Skinner, KT and Macdonald, A and Masood, O and Harris, RS and Fenton, TR and Periyasamy, M and Ali, S and Southgate, J},
doi = {10.1038/s41388-022-02235-8},
journal = {Oncogene},
pages = {2139--2151},
title = {Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer},
url = {http://dx.doi.org/10.1038/s41388-022-02235-8},
volume = {41},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Baker,SC
AU  - Mason,AS
AU  - Slip,RG
AU  - Skinner,KT
AU  - Macdonald,A
AU  - Masood,O
AU  - Harris,RS
AU  - Fenton,TR
AU  - Periyasamy,M
AU  - Ali,S
AU  - Southgate,J
DO  - 10.1038/s41388-022-02235-8
EP  - 2151
PY  - 2022///
SN  - 0950-9232
SP  - 2139
TI  - Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer
T2  - Oncogene
UR  - http://dx.doi.org/10.1038/s41388-022-02235-8
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000759404700002&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/s41388-022-02235-8
UR  - http://hdl.handle.net/10044/1/99825
VL  - 41
ER  -
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