Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage

Park, Jung Wook; Nickel, Kwangok P.; Torres, Alexandra D.; Lee, Denis; Lambert, Paul F.; Kimple, Randall J.

doi:10.1016/j.radonc.2014.08.026

Cited by 86 publications

(77 citation statements)

References 36 publications

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“…A DNA-damage/ repair response has been previously described in papillomavirus infection. 29 We did not observe γH2AX-and/or p53-positive cells in the decidua of HPV negative cases. However, the strongest signal for HPV was identified in the endometrial epithelium ( Figure 3, photomicrograph a HPV L1 IHC), with both strong endometrial cell cytoplasmic and nuclear staining using HPV-CISH (Figure 3, photomicrographs b and c).…”

Section: Hpv Detection In the Decidua And Endometriumcontrasting

confidence: 51%

“…We also observed an appropriate host response of DNA damage/repair and p53 activation, which was consistent with that previously described for papillomavirus infection. 29 To the best of our knowledge, this is the first study to describe in situ morphology of placental HPV infection and associated adverse clinical events, although further investigation is required to prove HPV is the etiologic agent. However, the popular assertion that HPV infection is of no clinical consequence in pregnancy maybe incorrect in light of our findings.…”

Section: Discussionmentioning

confidence: 90%

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A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

et al. 2015

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Viral infections are known to adversely affect pregnancy, but scant attention has been given to human papilloma virus (HPV) infection. We aimed to determine the molecular and histopathological features of placental HPV infection, in association with pregnancy complications including fetal growth restriction, pre-maturity, pre-eclampsia, and diabetes. Three hundred and thirty-nine placentae were selected based on the presence or absence of pregnancy complications. Five independent methods were used to identify HPV in the placenta, namely, immunohistochemistry for L1 viral capsid, in situ hybridization to high-risk HPV DNA, PCR, western blotting, and transmission electron microscopy. Pregnancy complications and uterine cervical smear screening results were correlated with placental HPV histopathology. In this study, which was deliberately biased towards complications, HPV was found in the decidua of 75% of placentae (253/339) and was statistically associated with histological acute chorioamnionitis (P o0.05). In 14% (35/253) of the HPV positive cases, HPV L1 immunoreactivity also occurred in the villous trophoblast where it was associated with a lymphohistiocytic villitis (HPV-LHV), and was exclusively of high-risk HPV type. HPV-LHV significantly associated with fetal growth restriction, preterm delivery, and pre-eclampsia (all P o0.05). All cases of pre-eclampsia (20/20) in our cohort had high-risk placental HPV. A further 55 cases (22%, 55/253) of HPV positive placentae had minimal villous trophoblast HPV L1 immunoreactivity, but a sclerosing pauci-immune villitis, statistically associated with diabetes (49.1%, 27/55, Po 0.05). For women with placental HPV, 33% (69/207) had an HPV-related positive smear result before pregnancy compared with (9.4% 8/85) of women with HPV-negative placentae (P = 0.0001). Our findings support further investigations to determine if vaccination of women and men will improve pregnancy outcomes. Modern Pathology (2015Pathology ( ) 28, 1369Pathology ( -1382 doi:10.1038/modpathol.2015 published online 21 August 2015 In the immune and hormonal modulated milieu of pregnancy, viruses are well known to infect the placenta, developing fetus, and neonate. The most common and important neoplastic driver of the lower uterine tract, human papillomavirus (HPV), 1 has been detected in the uterine cervix of 15-25% of pregnant women 2-6 and a cervical HPV infection during pregnancy has been associated with a higher incidence of spontaneous abortions, 7-9 premature rupture of the membranes, 10 spontaneous preterm labor, 11,12 pre-eclampsia, 13 and placental 'villitis' not otherwise specified. 12 HPV DNA has been detected in the placenta and amniotic fluid. 7,11,[14][15][16][17]11,16,18,and 31 have been shown to replicate in trophoblast cell lines, [18][19][20] where HPV infection decreased trophoblast number and trophoblast-endometrial cell adhesion in vitro. 19,20 We investigated for the presence of HPV in the placenta and carried out a histopathological and molecular cross-sectional study of 339 ...

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Section: Hpv Detection In the Decidua And Endometriumcontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 90%

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

et al. 2015

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“…Increased levels of Rad51 have been documented in a wide range of human tumors, including HPV-positive head and neck cancer cell lines, as well as HPV-positive cervical cancer lines (42,72). Moreover, increased expression of Rad51 is correlated with increased genomic instability through an elevation in spontaneous and aberrant HR (73,74).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Park et al demonstrated that expression of HPV16 E7 in oral keratinocytes is sufficient to increase protein levels of Rad51 (42). To determine if HPV31 E7 is also capable of increasing the levels of Rad51, as well as BRCA1, we examined HFKs retrovirally transduced and stably expressing HPV31 E6, E7, or E6/E7 in combination.…”

Section: Homologous Recombination Factors Rad51 and Brca1 Are Increasmentioning

confidence: 99%

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

Chappell

Gautam

et al. 2016

J Virol

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High-risk human papillomavirus 31 (HPV31)-positive cells exhibit constitutive activation of the ATM-dependent DNA damage response (DDR), which is necessary for productive viral replication. In response to DNA double-strand breaks (DSBs), ATM activation leads to DNA repair through homologous recombination (HR), which requires the principal recombinase protein Rad51, as well as BRCA1. Previous studies from our lab demonstrated that Rad51 and BRCA1 are expressed at high levels in HPV31-positive cells and localize to sites of viral replication. These results suggest that HPV may utilize ATM activity to increase HR activity as a means to facilitate viral replication. In this study, we demonstrate that high-risk HPV E7 expression alone is sufficient for the increase in Rad51 and BRCA1 protein levels. We have found that this increase occurs, at least in part, at the level of transcription. Studies analyzing protein stability indicate that HPV may also protect Rad51 and BRCA1 from turnover, contributing to the overall increase in cellular levels. We also demonstrate that Rad51 is bound to HPV31 genomes, with binding increasing per viral genome upon productive replication. We have found that depletion of Rad51 and BRCA1, as well as inhibition of Rad51's recombinase activity, abrogates productive viral replication upon differentiation. Overall, these results indicate that Rad51 and BRCA1 are required for the process of HPV31 genome amplification and suggest that productive replication occurs in a manner dependent upon recombination. IMPORTANCEProductive replication of HPV31 requires activation of an ATM-dependent DNA damage response, though how ATM activity contributes to replication is unclear. Rad51 and BRCA1 play essential roles in repair of double-strand breaks, as well as the restart of stalled replication forks through homologous recombination (HR). Given that ATM activity is required to initiate HR repair, coupled with the requirement of Rad51 and BRCA1 for productive viral replication, our findings suggest that HPV may utilize ATM activity to ensure localization of recombination factors to productively replicating viral genomes. The finding that E7 increases the levels of Rad51 and BRCA1 suggests that E7 contributes to productive replication by providing DNA repair factors required for viral DNA synthesis. Our studies not only imply a role for recombination in the regulation of productive HPV replication but provide further insight into how HPV manipulates the DDR to facilitate the productive phase of the viral life cycle. H uman papillomaviruses (HPVs) are small double-stranded DNA viruses approximately 8 kb in size that exhibit a preferential tropism for epithelial cells. High-risk mucosal HPV subtypes are the causative agents of cervical cancer and have been increasingly associated with anogenital, oropharyngeal, and head and neck cancers (1). The life cycle of HPV is intimately linked to the differentiation of its host cell, the keratinocyte (2). After exposure through a microwound in the stratified ep...

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“…7,8 Various OSCC cell lines have been established but only a few HPV positive OSCC cell lines are available for in vitro study. [9][10][11] In this study, we established and characterized cell lines from the HPV positive OSCC of 2 patients. Corresponding HPV positive cell lines were subsequently generated from nodal metastases following xenografting of these cell lines into nude mice.…”

Section: Introductionmentioning

confidence: 99%

In vitro3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines

Zhang

Rose

Lee

et al. 2015

Cancer Biology & Therapy

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The incidence of oropharyngeal squamous cell carcinoma (OSCC) is increasing due to the rising prevalence of human papillomavirus (HPV) positive OSCC. HPV positive OSCC is associated with better outcomes than HPV negative OSCC. Our aim was to explore the possibility that this favorable prognosis is due to the enhanced radiosensitivity of HPV positive OSCC. HPV positive OSCC cell lines were generated from the primary OSCCs of 2 patients, and corresponding HPV positive cell lines generated from nodal metastases following xenografting in nude mice. Monolayer and 3 dimensional (3D) culture techniques were used to compare the radiosensitivity of HPV positive lines with that of 2 HPV negative OSCC lines. Clonogenic and protein assays were used to measure survival post radiation. Radiation induced cell cycle changes were studied using flow cytometry. In both monolayer and 3D culture, HPV positive cells exhibited a heterogeneous appearance whereas HPV negative cells tended to be homogeneous. After irradiation, HPV positive cells had a lower survival in clonogenic assays and lower total protein levels in 3D cultures than HPV negative cells. Irradiated HPV positive cells showed a high proportion of cells in G1/S phase, increased apoptosis, an increased proliferation rate, and an inability to form 3D tumor clumps. In conclusion, HPV positive OSCC cells are more radiosensitive than HPV negative OSCC cells in vitro, supporting a more radiosensitive nature of HPV positive OSCC.

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Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage

Cited by 86 publications

References 36 publications

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

A clinicopathological study of episomal papillomavirus infection of the human placenta and pregnancy complications

Homologous Recombination Repair Factors Rad51 and BRCA1 Are Necessary for Productive Replication of Human Papillomavirus 31

In vitro3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines

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