HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage.
The role of the E6 oncoprotein from high-risk members of the α human papillomavirus genus in anogenital cancer has been well established. However, far less is known about the E6 protein from the β human papillomavirus genus (β-HPVs). Some β-HPVs potentially play a role in non-melanoma skin cancer de...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3395675?pdf=render |
| _version_ | 1818510121777496064 |
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| author | Nicholas A Wallace Kristin Robinson Heather L Howie Denise A Galloway |
| author_facet | Nicholas A Wallace Kristin Robinson Heather L Howie Denise A Galloway |
| author_sort | Nicholas A Wallace |
| collection | DOAJ |
| description | The role of the E6 oncoprotein from high-risk members of the α human papillomavirus genus in anogenital cancer has been well established. However, far less is known about the E6 protein from the β human papillomavirus genus (β-HPVs). Some β-HPVs potentially play a role in non-melanoma skin cancer development, although they are not required for tumor maintenance. Instead, they may act as a co-factor that enhances the carcinogenic potential of UV damage. Indeed, the E6 protein from certain β-HPVs (HPV 5 and 8) promotes the degradation of p300, a histone acetyl transferase involved in UV damage repair. Here, we show that the expression of HPV 5 and 8 E6 increases thymine dimer persistence as well as the likelihood of a UVB induced double strand break (DSB). Importantly, we provide a mechanism for the increased DNA damage by showing that both extended thymine dimer persistence as well as elevated DSB levels are dependent on the ability of HPV 8 E6 to promote p300 degradation. We further demonstrate that HPV 5 and 8 E6 expression reduces the mRNA and protein levels of ATR, a PI3 kinase family member that plays a key role in UV damage signaling, but that these levels remain unperturbed in cells expressing a mutated HPV 8 E6 incapable of promoting p300 degradation. We confirm that the degradation of p300 leads to a reduction in ATR protein levels, by showing that ATR levels rebound when a p300 mutant resistant to HPV 8 mediated degradation and HPV 8 E6 are co-transfected. Conversely, we show that ATR protein levels are reduced when p300 is targeted for degradation by siRNA. Moreover, we show the reduced ATR levels in HPV 5 and 8 E6 expressing cells results in delayed ATR activation and an attenuated ability of cells to phosphorylate, and as a result accumulate, p53 in response to UVB exposure, leading to significantly reduced cell cycle arrest. In conclusion, these data demonstrate that β-HPV E6 expression can enhance the carcinogenic potential of UVB exposure by promoting p300 degradation, resulting in a reduction in ATR levels, which leads to increased thymine dimer persistence and increased UVB induced DSBs. |
| first_indexed | 2024-12-10T22:54:54Z |
| format | Article |
| id | doaj.art-b82e3ed98da4426ca13bedefa12ce7f8 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-10T22:54:54Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-b82e3ed98da4426ca13bedefa12ce7f82022-12-22T01:30:18ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742012-01-0187e100280710.1371/journal.ppat.1002807HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage.Nicholas A WallaceKristin RobinsonHeather L HowieDenise A GallowayThe role of the E6 oncoprotein from high-risk members of the α human papillomavirus genus in anogenital cancer has been well established. However, far less is known about the E6 protein from the β human papillomavirus genus (β-HPVs). Some β-HPVs potentially play a role in non-melanoma skin cancer development, although they are not required for tumor maintenance. Instead, they may act as a co-factor that enhances the carcinogenic potential of UV damage. Indeed, the E6 protein from certain β-HPVs (HPV 5 and 8) promotes the degradation of p300, a histone acetyl transferase involved in UV damage repair. Here, we show that the expression of HPV 5 and 8 E6 increases thymine dimer persistence as well as the likelihood of a UVB induced double strand break (DSB). Importantly, we provide a mechanism for the increased DNA damage by showing that both extended thymine dimer persistence as well as elevated DSB levels are dependent on the ability of HPV 8 E6 to promote p300 degradation. We further demonstrate that HPV 5 and 8 E6 expression reduces the mRNA and protein levels of ATR, a PI3 kinase family member that plays a key role in UV damage signaling, but that these levels remain unperturbed in cells expressing a mutated HPV 8 E6 incapable of promoting p300 degradation. We confirm that the degradation of p300 leads to a reduction in ATR protein levels, by showing that ATR levels rebound when a p300 mutant resistant to HPV 8 mediated degradation and HPV 8 E6 are co-transfected. Conversely, we show that ATR protein levels are reduced when p300 is targeted for degradation by siRNA. Moreover, we show the reduced ATR levels in HPV 5 and 8 E6 expressing cells results in delayed ATR activation and an attenuated ability of cells to phosphorylate, and as a result accumulate, p53 in response to UVB exposure, leading to significantly reduced cell cycle arrest. In conclusion, these data demonstrate that β-HPV E6 expression can enhance the carcinogenic potential of UVB exposure by promoting p300 degradation, resulting in a reduction in ATR levels, which leads to increased thymine dimer persistence and increased UVB induced DSBs.http://europepmc.org/articles/PMC3395675?pdf=render |
| spellingShingle | Nicholas A Wallace Kristin Robinson Heather L Howie Denise A Galloway HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. PLoS Pathogens |
| title | HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. |
| title_full | HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. |
| title_fullStr | HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. |
| title_full_unstemmed | HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. |
| title_short | HPV 5 and 8 E6 abrogate ATR activity resulting in increased persistence of UVB induced DNA damage. |
| title_sort | hpv 5 and 8 e6 abrogate atr activity resulting in increased persistence of uvb induced dna damage |
| url | http://europepmc.org/articles/PMC3395675?pdf=render |
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