Genome-wide SiRNA Screen Identifies SMCX, EP400, and Brd4 As E2-dependent Regulators of Human Papillomavirus Oncogene Expression

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 6

PMID 20133580

Citations 87

Authors

Jennifer A Smith

Elizabeth A White

Mathew E Sowa

Maria L C Powell

Matthias Ottinger

J Wade Harper

Peter M Howley

Affiliations

Soon will be listed here.

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.

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