Article (Scientific journals)
Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair.
Bruyere, Diane; RONCARATI, Patrick; Lebeau, Alizée et al.
2023In Theranostics, 13 (3), p. 1130 - 1149
Peer Reviewed verified by ORBi
 

Files


Full Text
Bruyere Theranostics 2023.pdf
Publisher postprint (5.26 MB) Creative Commons License - Attribution
Download

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
DNA damage and repair; human papillomavirus; protein-protein interactome.; radiotherapy; Oncogene Proteins, Viral
Abstract :
[en] Rationale: Whatever the mucosa primary infected, HPV-positive cancers are traditionally associated with a favorable outcome, attributable to a high sensitivity to radiation therapy. However, the direct impact of viral E6/E7 oncoproteins on the intrinsic cellular radiosensitivity (and, globally, on host DNA repair) remains mostly speculative. Methods: Using several isogenic cell models expressing HPV16 E6 and/or E7, the effect of viral oncoproteins on global DNA damage response was first investigated by in vitro/in vivo approaches. The binary interactome of each individual HPV oncoprotein with factors involved in the various host DNA damage/repair mechanisms was then precisely mapped by Gaussia princeps luciferase complementation assay (and validated by co-immunoprecipitation). The stability/half-life of protein targets for HPV E6 and/or E7 as well as their subcellular localizations were determined. At last, the host genome integrity following E6/E7 expression and the synergy between radiotherapy and compounds targeting DNA repair were analyzed. Results: We first showed that the sole expression of one viral oncoprotein from HPV16 was able to significantly increase the sensitivity to irradiation of cells without affecting their basal viability parameters. In total, 10 novel targets (CHEK2, CLK2, CLK2/3, ERCC3, MNAT1, PER1, RMI1, RPA1, UVSSA and XRCC6) for E6 and 11 (ALKBH2, CHEK2, DNA2, DUT, ENDOV, ERCC3, PARP3, PMS1, PNKP, POLDIP2 and RBBP8) for E7 were identified. Importantly, not degraded following their interaction with E6 or E7, these proteins have been shown to be less linked to host DNA and to colocalize with HPV replication foci, denoting their crucial implication in viral life cycle. Finally, we found that E6/E7 oncoproteins globally jeopardize host genome integrity, increase the cellular sensitivity to DNA repair inhibitors and enhance their synergy with radiotherapy. Conclusion: Taken together, our findings provide a molecular insight into the direct hijacking of host DNA damage/repair responses by HPV oncoproteins, demonstrate the significant impact of this phenomenon on both intrinsic cellular radiosensitivity and host DNA integrity and suggest novel connected therapeutic vulnerabilities.
Disciplines :
Oncology
Author, co-author :
Bruyere, Diane;  Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, 4000 Liege, Belgium
RONCARATI, Patrick ;  Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Lebeau, Alizée ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire
Lerho, Thomas ;  Université de Liège - ULiège > GIGA
Poulain, Florian;  Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
Hendrick, Elodie ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Experimental Pathology
Pilard, Charlotte ;  Université de Liège - ULiège > GIGA - MASSGPFS
Reynders, Célia  ;  Université de Liège - ULiège > GIGA
Ancion, Marie ;  Université de Liège - ULiège > GIGA
Luyckx, Margaux ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Experimental Pathology
Renard, Michael ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Jacob, Yves;  Unit of Molecular Genetics of RNA Viruses, UMR 3569, CNRS, Pasteur Institute, University of Paris Diderot, 75015 Paris, France
Twizere, Jean-Claude  ;  Université de Liège - ULiège > GIGA > GIGA Molecular Biology of Diseases - Viral Interactomes Network
Peiffer, Raphaël  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Peulen, Olivier  ;  Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory
Delvenne, Philippe ;  Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Hubert, Pascale  ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques
McBride, Alison;  Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
Gillet, Nicolas ;  Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Microbial technologies ; Namur Research Institute for Life Sciences (NARILIS), Integrated Veterinary Research Unit (URVI), University of Namur, Namur, Belgium
Masson, Murielle;  Biothechnology Superior School, UMR 7242, CNRS, University of Strasbourg, 67412 Illkirch, France
Herfs, Michael ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques
More authors (11 more) Less
Language :
English
Title :
Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair.
Publication date :
2023
Journal title :
Theranostics
eISSN :
1838-7640
Publisher :
Ivyspring International Publisher, Australia
Volume :
13
Issue :
3
Pages :
1130 - 1149
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 21 February 2023

Statistics


Number of views
135 (28 by ULiège)
Number of downloads
43 (4 by ULiège)

Scopus citations®
 
1
Scopus citations®
without self-citations
0
OpenCitations
 
0

Bibliography


Similar publications



Contact ORBi