Abstract
An essential step in the pathogenesis of human papillomavirus (HPV)-associated cancers is the dysregulated expression of the viral oncogenes. The papillomavirus E2 protein can silence the long control region (LCR) promoter that controls viral E6 and E7 oncogene expression. The mechanisms by which E2 represses oncogene expression and the cellular factors through which E2 mediates this silencing are largely unknown. We conducted an unbiased, genome-wide siRNA screen and series of secondary screens that identified 96 cellular genes that contribute to the repression of the HPV LCR. In addition to confirming a role for the E2-binding bromodomain protein Brd4 in E2-mediated silencing, we identified a number of genes that have not previously been implicated in E2 repression, including the demethylase JARID1C/SMCX as well as EP400, a component of the NuA4/TIP60 histone acetyltransferase complex. Each of these genes contributes independently and additively to E2-mediated silencing, indicating that E2 functions through several distinct cellular complexes to repress E6 and E7 expression.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Cell Cycle Proteins
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Cell Line, Tumor
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Female
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Gene Expression Regulation, Viral*
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Gene Silencing
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Genome-Wide Association Study
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HeLa Cells
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Histone Demethylases
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Human papillomavirus 18 / genetics*
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Humans
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins, Viral / genetics*
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Oncogene Proteins, Viral / metabolism
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Oxidoreductases, N-Demethylating / genetics
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Oxidoreductases, N-Demethylating / metabolism*
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Papillomavirus Infections / metabolism
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Papillomavirus Infections / virology
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RNA, Small Interfering / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Uterine Cervical Neoplasms / metabolism
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Uterine Cervical Neoplasms / virology
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Viral Proteins / metabolism
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Virus Replication / genetics
Substances
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BRD4 protein, human
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2 protein, Bovine papillomavirus
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E2 protein, Human papillomavirus type 16
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E6 protein, Human papillomavirus type 18
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E7 protein, Human papillomavirus type 18
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Nuclear Proteins
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Oncogene Proteins, Viral
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RNA, Small Interfering
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Transcription Factors
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Viral Proteins
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Histone Demethylases
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KDM5C protein, human
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Oxidoreductases, N-Demethylating
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DNA Helicases
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EP400 protein, human