Abstract
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.
Highlights
Human papillomaviruses (HPV) have double stranded DNA genomes of around 8 kb and productively infect only the epithelium
The other major anatomical site where high risk HPV (HR-HPV) cause cancer is in the oropharyngeal region (HPV + OPC, oropharyngeal carcinoma), homologous recombination (HR)-HPV positive tumors can be found throughout the oral cavity [2,3,4]
We propose that the activation of the DNA damage response (DDR) in HPV positive cells originates from the replication ofthe theE1–E2
Summary
Human papillomaviruses (HPV) have double stranded DNA genomes of around 8 kb and productively infect only the epithelium. While the current prophylactic vaccines targeting both LR-HPV and HR-HPV will reduce the disease burden on future generations, it remains a priority to develop therapeutics targeting these viruses for several reasons. It is possible that over the decades the viruses targeted by the vaccines may evolve to evade vaccine targeting and persist in causing disease. In the developing world where most of the HR-HPV deaths occur, there has been a limited ability to introduce the prophylactic vaccine for financial and/or logistical reasons. Novel therapeutic approaches to combat HPV infections are required and enhancing our understanding of the HPV life cycle will assist in identifying such approaches.
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