Dangerous Liaisons: Long-Term Replication with an Extrachromosomal HPV Genome

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.

The guardian of the genome meets a viral master gene regulator at a biomolecular condensate

“…The HPV E2 protein is the master regulator of the virus life cycle, with main roles involving the control of gene transcription and viral genome replication (McBride, 2013). E2 role in transcription is well characterized, it functions primarily by recruiting cellular factors to the viral genomes, which activate or repress transcriptional processes upon specific binding to the viral genome in a dose-dependent manner (McBride, 2013; Warburton et al, 2021). Additionally, E2 acts as a loading factor for the viral helicase E1 at the HPV origin of replication and in late stages of replication has crucial roles in genome maintenance and partition (Warburton et al, 2021).…”

“…E2 role in transcription is well characterized, it functions primarily by recruiting cellular factors to the viral genomes, which activate or repress transcriptional processes upon specific binding to the viral genome in a dose-dependent manner (McBride, 2013; Warburton et al, 2021). Additionally, E2 acts as a loading factor for the viral helicase E1 at the HPV origin of replication and in late stages of replication has crucial roles in genome maintenance and partition (Warburton et al, 2021). The E2 proteins are around 400 amino acid polypeptides consisting of an N-terminal transactivation domain (ca.…”

“…Interestingly, p53 was subsequently found at the viral replication sites of SV40, herpes simplex virus (HSV), cytomegalovirus (CMV) and adenovirus (Fortunato and Spector, 1998; Gannon and Lane, 1987; Konig et al, 1999; Wilcock and Lane, 1991). Replication of HPV is carried out at so-called replication foci or HPV E1/E2 foci, containing the viral helicase E1 and E2 (Warburton et al, 2021). These E1/E2 foci represent viral replication factories, and they recruit DNA damage response (DDR) proteins including p53 phosphorylated at serine 15 (Sakakibara et al, 2011; Warburton et al, 2021).…”

“…Replication of HPV is carried out at so-called replication foci or HPV E1/E2 foci, containing the viral helicase E1 and E2 (Warburton et al, 2021). These E1/E2 foci represent viral replication factories, and they recruit DNA damage response (DDR) proteins including p53 phosphorylated at serine 15 (Sakakibara et al, 2011; Warburton et al, 2021). E2 protein was shown to bind to p53 by pull-down assays in vitro and in cells (Massimi et al, 1999; Parish et al, 2006).…”

Human Papillomavirus Genome Copy Number Is Maintained by S Phase Amplification, Leakage to the Cytosol during Mitosis and Lysosomal Degradation in G1 Phase

“…In addition, regulatory viral factors such as the E8^E2 repressor have been shown to regulate genome copy number (5,6). During maintenance, genome is replicated via the bi-directional mode (1,7,8). Several reports have suggested that differentiation-induced genome amplification utilizes a rolling circle mechanism based mainly on data derived from the analysis of two-dimensional gel electrophoresis (8)(9)(10)(11).…”