Why Human Papillomaviruses Activate the DNA Damage Response (DDR) and How Cellular and Viral Replication Persists in the Presence of DDR Signaling

Viruses. 2017 Sep 21;9(10):268. doi: 10.3390/v9100268.


Human papillomaviruses (HPV) require the activation of the DNA damage response (DDR) in order to undergo a successful life cycle. This activation presents a challenge for the virus and the infected cell: how does viral and host replication proceed in the presence of a DDR that ordinarily arrests replication; and how do HPV16 infected cells retain the ability to proliferate in the presence of a DDR that ordinarily arrests the cell cycle? This raises a further question: why do HPV activate the DDR? The answers to these questions are only partially understood; a full understanding could identify novel therapeutic strategies to target HPV cancers. Here, we propose that the rapid replication of an 8 kb double stranded circular genome during infection creates aberrant DNA structures that attract and activate DDR proteins. Therefore, HPV replication in the presence of an active DDR is a necessity for a successful viral life cycle in order to resolve these DNA structures on viral genomes; without an active DDR, successful replication of the viral genome would not proceed. We discuss the essential role of TopBP1 in this process and also how viral and cellular replication proceeds in HPV infected cells in the presence of DDR signals.

Keywords: ATM (ataxia-telangiectasia mutated); ATR (ataxia telangiectasia and Rad3 related); DNA damage response; DNA damage signaling; E1; E2; HPV; MRN (Mre11-Rad50-Nbs1); TopBP1; cervical cancer; head and neck cancer; homologous recombination; human papillomavirus; initiation; life cycle; replication.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Carrier Proteins / physiology
  • Cell Cycle / physiology
  • DNA Damage*
  • DNA Repair*
  • DNA Replication*
  • DNA-Binding Proteins / physiology
  • Genome, Viral
  • Host-Pathogen Interactions / physiology*
  • Human papillomavirus 16 / physiology
  • Humans
  • Nuclear Proteins / physiology
  • Papillomaviridae / physiology*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / virology*
  • Viral Proteins / physiology
  • Virus Replication*


  • Carrier Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • TOPBP1 protein, human
  • Viral Proteins