Human Papillomavirus E7 Induces Rereplication in Response to DNA Damage

Fan, Xueli; Liu, Yingwang; Heilman, Susan Ann; Chen, Jason J.

doi:10.1128/jvi.02038-12

Cited by 34 publications

(53 citation statements)

References 60 publications

(68 reference statements)

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“…As transfection efficiencies in keratinocytes are not very high, we included RPE1 cells. RPE1 cells expressing the wild-type E7 (RPE1-E7) and vector control (RPE1-vector) have been used in our recent HPV-related functional studies (16,84,85). Similarly to what was observed in keratinocytes, WDHD1 mRNA levels were increased (ϳ2-fold) in E7-expressing RPE1 cells (Fig.…”

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 49%

“…Cells of the human telomerase reverse transcriptase-expressing human retinal pigment epithelium cell line RPE1 were maintained in a 1:1 dilution of DMEM-Ham's F-12 medium plus 10% FBS. PHK and NIKS cells expressing HPV-16 E7 and RPE1 cells expressing HPV-16 E7 or HPV-6 E7 were established using a pBabe retroviral system as described previously (16). Populations of infected cells were pooled and expanded.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently demonstrated that cells expressing HPV-16 E7 undergo rereplication upon DNA damage and that the DNA replication-initiating factor Cdt1 plays an important role in this process (16). Since WDHD1 has been implicated as a DNA replication-initiating factor (22), we examined its potential role in E7-induced rereplication.…”

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 99%

“…It is known that E7 is involved in transcriptional regulation, partly through degradation of pRb and release of E2F. E7 has been known to regulate the DNA damage response (16). In fact, E7 also induces DNA damage (63,64).…”

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 99%

“…Rereplication may lead to not only polyploidy but also gene amplification, DNA fragmentation, DNA breaks, and cellular DNA damage response (13)(14)(15). We recently demonstrated that HPV-16 E7 induces rereplication and that the cellular DNA replication initiation factor Cdt1 plays a role in this process (16).…”

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confidence: 99%

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Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Yang

Zhang

Gao

et al. 2016

J Virol

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The E7 oncoprotein of the high-risk human papillomavirus (HPV) plays a major role in HPV-induced carcinogenesis. E7 abrogates the G 1 cell cycle checkpoint and induces genomic instability, but the mechanism is not fully understood. In this study, we performed RNA sequencing (RNA-seq) to characterize the transcriptional profile of keratinocytes expressing HPV 16 (HPV-16) E7. At the transcriptome level, 236 genes were differentially expressed between E7 and vector control cells. A subset of the differentially expressed genes, most of them novel to E7-expressing cells, was further confirmed by real-time PCR. Of interest, the activities of multiple transcription factors were altered in E7-expressing cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were investigated. The upregulated genes were enriched in cell cycle and DNA replication, as well as in the DNA metabolic process, transcription, DNA damage, DNA repair, and nucleotide metabolism. Specifically, we focused our studies on the gene encoding WDHD1 (WD repeat and high mobility group [HMG]-box DNA-binding protein), one of the genes that was upregulated in E7-expressing cells. WDHD1 is a component of the replisome that regulates DNA replication. Recent studies suggest that WDHD1 may also function as a DNA replication initiation factor as well as a G 1 checkpoint regulator. We found that in E7-expressing cells, the steady-state level of WDHD1 protein was increased along with the half-life. Moreover, downregulation of WDHD1 reduced E7-induced G 1 checkpoint abrogation and rereplication, demonstrating a novel function for WDHD1. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. IMPORTANCEThe high-risk HPV types induce cervical cancer and encode an E7 oncoprotein that plays a major role in HPV-induced carcinogenesis. However, the mechanism by which E7 induces carcinogenesis is not fully understood; specific anti-HPV agents are not available. In this study, we performed RNA-seq to characterize transcriptional profiling of keratinocytes expressing HPV-16 E7 and identified more than 200 genes that were differentially expressed between E7 and vector control cells. Through bioinformatics analysis, pathways altered in E7-expressing cells were identified. Significantly, the WDHD1 gene, one of the genes that is upregulated in E7-expressing cells, was found to play an important role in E7-induced G 1 checkpoint abrogation and rereplication. These studies shed light on mechanisms by which HPV induces genomic instability and have therapeutic implications. H uman papillomaviruses (HPVs) are small DNA viruses that replicate in squamous epithelia. Specific types of HPV (highrisk HPVs) are the causative agents for cervical and several other cancers (1). The transforming properties of high-risk HPVs such as HPV 16 (HPV-16) primarily depend on E7 as well as E6 oncogenes (1, 2). HPV E6 and E7 proteins promote the degradation of p53 and pRb, respectively (3, 4). E7 from the high-risk...

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Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 49%

Section: Methodsmentioning

confidence: 99%

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 99%

Section: Gene Expression Profiling Of Hpv-16 E7-expressing Cellsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Role of WDHD1 in Human Papillomavirus-Mediated Oncogenesis Identified by Transcriptional Profiling of E7-Expressing Cells

Yang

Zhang

Gao

et al. 2016

J Virol

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Melatonin: A new inhibitor agent for cervical cancer treatment

Shafabakhsh

Reíter

Mirzaei

et al. 2019

Journal Cellular Physiology

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Cervical cancer is one of the most common cancers between women and is known as the third leading cause of female cancer related deaths annually. Its detection in early stages allows it to be a preventable and generally treatable disease. Increasing evidence revealed, a variety of internal and external factors are associated with initiation and progression of cervical cancer pathogenesis. Human papilloma virus infection is found as a major cause of cervical cancer. Other molecular and biochemical alterations as well as genetic and epigenetic changes are related cervical cancer progression. Current treatment options often have severe side effects and toxicities thus, new adjuvant agents having synergistic effects and ability to decrease different side effects and toxicities are needed. Melatonin is an indolamine compound secreted from the pineal gland which shows wide range anticancer activities. A large amount of studies indicated inhibitory effects of melatonin against various types of cancers. In addition, experimental evidence reports inhibitory effects of melatonin as an adjuvant therapy on cervical cancer by targeting a sequence of different molecular mechanisms. Herein, for first time, we summarized anticervical cancer effects of melatonin and its underlying molecular mechanisms.

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