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Author Notes:

Address Correspondence to Cary Moody, camoody@med.unc.edu

Subjects:

Research Funding:

This project was supported by NIH grant 1R01CA181581 and American Cancer Society grant A14-0113 (to C.A.M.), and NIH grants R01 GM104198 and R01 AI049781 (to B.K.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Virology
  • Human papillomavirus
  • Replication
  • DNA damage response
  • Pathogenesis
  • DNA-DAMAGE RESPONSE
  • ONCOGENE-INDUCED SENESCENCE
  • HUMAN-PAPILLOMAVIRUS TYPE-31
  • RIBONUCLEOTIDE REDUCTASE R2
  • DEPENDENT UP-REGULATION
  • LATE VIRAL FUNCTIONS
  • S-PHASE
  • EPITHELIAL DIFFERENTIATION
  • LIFE-CYCLE
  • NUCLEOTIDE-METABOLISM

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

Tools:

Journal Title:

Virology

Volume:

Volume 499

Publisher:

, Pages 383-396

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 Elsevier Inc.

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