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Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair
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 h...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Ivyspring International Publisher
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925306/ https://www.ncbi.nlm.nih.gov/pubmed/36793865 http://dx.doi.org/10.7150/thno.78091 |
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author | Bruyere, Diane Roncarati, Patrick Lebeau, Alizee Lerho, Thomas Poulain, Florian Hendrick, Elodie Pilard, Charlotte Reynders, Celia Ancion, Marie Luyckx, Margaux Renard, Michael Jacob, Yves Twizere, Jean-Claude Peiffer, Raphael Peulen, Olivier Delvenne, Philippe Hubert, Pascale McBride, Alison Gillet, Nicolas Masson, Murielle Herfs, Michael |
author_facet | Bruyere, Diane Roncarati, Patrick Lebeau, Alizee Lerho, Thomas Poulain, Florian Hendrick, Elodie Pilard, Charlotte Reynders, Celia Ancion, Marie Luyckx, Margaux Renard, Michael Jacob, Yves Twizere, Jean-Claude Peiffer, Raphael Peulen, Olivier Delvenne, Philippe Hubert, Pascale McBride, Alison Gillet, Nicolas Masson, Murielle Herfs, Michael |
author_sort | Bruyere, Diane |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9925306 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Ivyspring International Publisher |
record_format | MEDLINE/PubMed |
spelling | pubmed-99253062023-02-14 Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair Bruyere, Diane Roncarati, Patrick Lebeau, Alizee Lerho, Thomas Poulain, Florian Hendrick, Elodie Pilard, Charlotte Reynders, Celia Ancion, Marie Luyckx, Margaux Renard, Michael Jacob, Yves Twizere, Jean-Claude Peiffer, Raphael Peulen, Olivier Delvenne, Philippe Hubert, Pascale McBride, Alison Gillet, Nicolas Masson, Murielle Herfs, Michael Theranostics Research Paper 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. Ivyspring International Publisher 2023-01-31 /pmc/articles/PMC9925306/ /pubmed/36793865 http://dx.doi.org/10.7150/thno.78091 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
spellingShingle | Research Paper Bruyere, Diane Roncarati, Patrick Lebeau, Alizee Lerho, Thomas Poulain, Florian Hendrick, Elodie Pilard, Charlotte Reynders, Celia Ancion, Marie Luyckx, Margaux Renard, Michael Jacob, Yves Twizere, Jean-Claude Peiffer, Raphael Peulen, Olivier Delvenne, Philippe Hubert, Pascale McBride, Alison Gillet, Nicolas Masson, Murielle Herfs, Michael Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title | Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title_full | Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title_fullStr | Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title_full_unstemmed | Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title_short | Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair |
title_sort | human papillomavirus e6/e7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host dna damage repair |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9925306/ https://www.ncbi.nlm.nih.gov/pubmed/36793865 http://dx.doi.org/10.7150/thno.78091 |
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