Abstract
Papillomaviruses cause persistent, and usually self-limiting, infections in the mucosal and cutaneous surfaces of the host epithelium. However, in some cases, infection with an oncogenic HPV can lead to cancer. The viral genome is a small, double-stranded circular DNA molecule that is assembled into nucleosomes at all stages of infection. The viral minichromosome replicates at a low copy number in the nucleus of persistently infected cells using the cellular replication machinery. When the infected cells differentiate, the virus hijacks the host DNA damage and repair pathways to replicate viral DNA to a high copy number to generate progeny virions. This strategy is highly effective and requires a close association between viral and host chromatin, as well as cellular processes associated with DNA replication, repair, and transcription. However, this association can lead to accidental integration of the viral genome into host DNA, and under certain circumstances integration can promote oncogenesis. Here we describe the fate of viral DNA at each stage of the viral life cycle and how this might facilitate accidental integration and subsequent carcinogenesis.
Highlights
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Citation: Warburton, A.; Della Fera, A.N.; McBride, A.A
This association was first demonstrated with a bovine papillomavirus (BPV1) genome [32,33] but has been more difficult to observe with the lower copy number human papillomaviruses (HPVs) genomes
High levels of E1 and E2 proteins are expressed in differentiated cells to amplify the viral DNA [65,66,67], and HPVs activate both ATM and ATR (ATM and Rad3-related) DNA damage response pathways to support the synthesis of viral DNA at nuclear replication foci in differentiated cells [44,68]
Summary
440 different human papillomaviruses (HPVs) have been described [1]. They are classified into five different genera that are named Alpha, Beta, Gamma, Mu, and Nupapillomaviruses. A subset of these HPVs is considered oncogenic, and persistent infection with these viruses can result in anogenital or oropharyngeal cancers [3]. Viruses are shown in red/orange and low-risk viruses in green/blue. Viruses that have been found to be frequently integrated are indicated with an asterisk * Those viruses that have been found to beon frequently indicated with an asterisk
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