HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

Daniel C. Anacker, Heather L. Aloor, Caitlin N. Shepard, Gina M. Lenzi, Bryan A. Johnson, Baek Kim, Cary A. Moody

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Productive replication of human papillomaviruses (HPV) is restricted to the uppermost layers of the differentiating epithelia. How HPV ensures an adequate supply of cellular substrates for viral DNA synthesis in a differentiating environment is unclear. Here, we demonstrate that HPV31 positive cells exhibit increased dNTP pools and levels of RRM2, a component of the ribonucleotide reductase (RNR) complex, which is required for de novo synthesis of dNTPs. RRM2 depletion blocks productive replication, suggesting RRM2 provides dNTPs for viral DNA synthesis in differentiating cells. We demonstrate that HPV31 regulates RRM2 levels through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response, which is essential to combat replication stress upon entry into S-phase, as well as for productive replication. Our findings suggest a novel way in which viral DNA synthesis is regulated through activation of ATR and Chk1 and highlight an intriguing new virus/host interaction utilized for viral replication.

Original languageEnglish (US)
Pages (from-to)383-396
Number of pages14
JournalVirology
Volume499
DOIs
StatePublished - Dec 1 2016

Keywords

  • DNA damage response
  • Human papillomavirus
  • Pathogenesis
  • Replication

ASJC Scopus subject areas

  • Virology

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