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

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

Molly L Bristol  1 , Dipon Das  2 , Iain M Morgan  3   4
Affiliations
Review

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

Molly L Bristol et al. Viruses. .

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.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HPV E1–E2 mediated replication has the capacity to directly activate DNA damage repair pathways. Following infection, the viral genome must be quickly amplified to 20–50 copies per cell. This replication potentially generates “onion skin” structures causing torsional stress promoting the formation of single stranded DNA and double strand breaks that would be recognized as DNA damage by the cell. Therefore, during the establishment phase of the cell cycle, we propose that HPV replication would activate a local DDR via aberrant DNA structures on the viral genome. Failure to activate this response would result in failure to replicate.
Figure 2
Figure 2
TopBP1 is a key component of correct HPV E1–E2 mediated DNA replication. The E2 protein recognizes the viral origin of replication (represented by the black line) and therefore serves as the viral origin recognition complex. It then recruits a host of proteins to the origin via protein-protein interactions, including the viral helicase E1 and TopBP1, to form the replication initiation complex. TopBP1 can interact with both E2 and E1 and is known to recruit DNA polymerases to mammalian replication complexes. Following the initiation of replication, the E1 helicase and host polymerases can then begin to replicate the viral genome. The number and function of host proteins required for this process remains unclear. Only one copy of the di-hexameric E1 complex required for replication is shown for the sake of simplicity.
Figure 3
Figure 3
TopBP1 is a key protein initiating and coordinating DDR signaling at HPV replication centers. Figure 1 indicates that onion skin DNA replication can be formed on HPV genomes during the initial phases of infection and we propose that this would activate the DDR. Figure 2 briefly summarizes the role of TopBP1 in coordinating the initiation of HPV replication. In this figure, we demonstrate the key role of TopBP1 in both initiating and controlling DDR signaling at HPV replication forks. Torsional stress during onion skin replication would generate both stretches of single stranded DNA (bottom panel) and also double strand breaks (top panel). Both of these DNA structures would generate proposed localized DDR signaling, and TopBP1 is key to the activation of both ATR and ATM. HPV replication in the absence of TopBP1 is highly mutagenic, demonstrating that it is a key component of the HPV replication process. The precise order, sequence, function, and components of HPV replication remain to be fully elucidated. The black lines represent DNA strands. The blue “circular” line represents phosphorylation events. See text for details.
Figure 4
Figure 4
HPV replication is not arrested by DDR signaling. The failure of DDR signaling to arrest E1–E2 mediated DNA replication is essential for the viral life cycle as an active DDR is required for viral replication. However, host cell replication is arrested in the presence of DDR signaling via the phosphorylation of MCM proteins by ATR (and ATM). This uncouples the MCM helicase from DNA polymerases allowing for replication arrest, repair, and restart (top panel). The virus does not have this luxury as it must replicate in the presence of a DDR (bottom panel); therefore, HPV replication has an inherent instability as replication in the presence of external DNA damaging agents is mutagenic as viral replication is not arrested. This mutagenesis would provide substrates for viral genome integration into that of the host, a hallmark of cervical cancer. The DDR signaling generated by E1–E2 replication must be controlled locally to avoid viral arrest of host cell replication via MCM-polymerase uncoupling; such an arrest would be fatal for the viral life cycle. The black lines represent DNA strands. The blue “circular” line represents phosphorylation events.
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