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Abrogation of the Brd4-positive transcription elongation factor B complex by papillomavirus E2 protein contributes to

Junpeng Yan1, Qing Li, Sam Lievens

  • 1Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Journal of Virology
|October 23, 2009
PubMed

Insights

Human papillomavirus (HPV) E2 protein binding to Brd4 inhibits P-TEFb recruitment, repressing viral oncogene expression from integrated HPV genomes in cancer cells.

Area of Science:

  • Molecular Biology
  • Virology
  • Cancer Biology

Background:

  • Brd4, a cellular bromodomain protein, interacts with papillomavirus (PV) E2 protein, aiding viral episome maintenance and repressing oncogene expression in HPV-positive cancers.
  • Brd4 recruits positive transcription elongation factor b (P-TEFb) to promote RNA polymerase II phosphorylation, crucial for gene expression.

Purpose of the Study:

  • To elucidate the mechanism by which HPV E2 protein binding to Brd4 represses viral oncogene expression from integrated HPV genomes.
  • To investigate the role of the Brd4-P-TEFb interaction in HPV oncogene transcription.

Main Methods:

  • Investigated the interaction between E2, Brd4, and P-TEFb in HPV-positive cancer cells (HeLa and CaSki).
  • Utilized a Brd4 bromodomain dominant-negative inhibitor to disrupt the Brd4-P-TEFb complex.
  • Assessed the impact on viral oncogene E6/E7 transcription and recruitment of P-TEFb to viral chromatin.

Main Results:

  • E2 binding to Brd4 inhibits the interaction between Brd4 and P-TEFb.
  • E2 binding abrogates P-TEFb recruitment to integrated HPV chromatin, inactivating P-TEFb and repressing E6/E7 oncogene expression.
  • Disruption of the Brd4-P-TEFb complex also reduces HPV E6/E7 oncogene expression.

Conclusions:

  • Brd4's recruitment of P-TEFb to viral chromatin is essential for HPV oncogene expression.
  • The E2-mediated abrogation of the Brd4-P-TEFb interaction provides a mechanism for repressing viral oncogenes in HPV-associated cancers.

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