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Review
. 2014 Jun:26:30-42.
doi: 10.1016/j.semcancer.2013.12.003. Epub 2014 Jan 8.

Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses

Nicholas A Wallace  1 , Denise A Galloway  2
Affiliations
Review

Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses

Nicholas A Wallace et al. Semin Cancer Biol. 2014 Jun.

Abstract

In general, the interplay among viruses and DNA damage repair (DDR) pathways can be divided based on whether the interaction promotes or inhibits the viral lifecycle. The propagation of human papillomaviruses is both promoted and inhibited by DDR proteins. As a result, HPV proteins both activate repair pathways, such as the ATM and ATR pathways, and inhibit other pathways, most notably the p53 signaling pathway. Indeed, the role of HPV proteins, with regard to the DDR pathways, can be divided into two broad categories. The first set of viral proteins, HPV E1 and E2 activate a DNA damage response and recruit repair proteins to viral replication centers, where these proteins are likely usurped to replicate the viral genome. Because the activation of the DDR response typically elicits a cell cycle arrest that would impeded the viral lifecycle, the second set of HPV proteins, HPV E6 and E7, prevents the DDR response from pausing cell cycle progression or inducing apoptosis. This review provides a detailed account of the interactions among HPV proteins and DDR proteins that facilitate HPV propagation.

Keywords: DNA damage repair; HPV; HPV replication.

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Conflict of interest statement

Conflict of Interest Statement:

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Brief Overview of DNA Damage Repair: Three common types of DNA damage are depicted in this image as well as an summary of the pathways/proteins that are activated in response to each type of damage. A. A double strand break DNA break (DSB) most often results in the activation, by phosphorylation (indicated in this figure by a circled p), of the PI3 kinase ATM. Multiple pathways are downstream of ATM including homology dependent DSB repair (HR), non-homologous end joining (NHEJ), the Fanconi Anemia pathway (FANC), as well as the p53 signaling pathway. B. In response to intrastrand crosslinks (crosslink), ATR and its interacting partner ATRIP become activated and phosphorylated leading to the induction of several downstream pathways. The activated ATR/ATRIP complex induces the Fanconi Anemia repair and Nucleotide Excision Repair (NER) pathways, as well as the p53 signaling pathway. C. Finally, a single strand DNA break (SSB) causes the activation of both PARP1 and the MRN (MRE11, RAD50, NBS1) complex and ultimately together with XRCC1, DNA Ligase III as well as multiple other repair proteins fixes the lesion.
Figure 2
Figure 2
HPV Replication and the Cellular DNA Damage Response: A. HPV E1 and E2 along with the HPV genome form viral replication centers. The replication center is depicted here along with the numerous DNA damage repair proteins that they are known to colocalize with. Several more direct interactions are also shown. Particular, HPV E2 tethers the viral genome to the cellular genome via an interaction with TOPBP1. Furthermore, HPV E1 and E2 colocalize with proteins involved in p53, ATR, and ATM signaling as well as enzymes involved in the homology dependent and independent repair of DSBs. Finally, viral replication sites also colocalize to areas of phosphorylated H2AX, represented by a circled p. B. This figure shows a depiction of epithelium, HPV-infected cells are shown in lighter hues. Viral replication centers and the associated repair proteins depicted in Figure 2A are shown here as yellow dots. The magnitude of the induction of the cellular DNA damage response by HPV replication varies greatly between viral genome maintenance and viral genome amplification. During maintenance, the HPV genome is replicated is synchronized with cellular replication and viral copy number is relatively low. In contrast, as HPV-infected cells differentiate, the virus enters the amplification phase of its life cycle, when viral replication centers can greatly outnumber chromosomes. This increased HPV replication accompanying the transition from viral genome maintenance to amplification is depicted by both more numerous and larger yellow circles denoting both increase in quantity of viral replication centers as well as the enlarged DNA damage foci associated with this period of the viral lifecycle.
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