Trends in Microbiology
ReviewCatching HPV in the Homologous Recombination Cookie Jar
Section snippets
Understanding Human Papillomaviruses and Host DNA Machinery to Combat Disease
According to the World Health Organization, human papillomavirus (HPV) infections cause cancers that kill someone about every 90 s. HPV transforms tissues throughout the anogenital tract and oral cavity [1]. There are several formulations of prophylactic vaccines against these infections, each with an admirable safety profile, that provide immunity against the deadliest HPV infections [2]. In the developed world, their primary limitation is under-utilization resulting from vaccine hesitancy and
HPV’s Reliance on Host Homologous Recombination Proteins
HPV replication is not uniformly dependent on homologous recombination proteins. The HPV life cycle has two distinct phases (Figure 2A). The first begins with the virus infecting epithelial cells, gaining access to basal keratinocytes through microabrasions. When these cells divide laterally, the viral genome replicates along with the cell, keeping a steady number of genomes. This is the virus’s maintenance phase [17]. Homologous recombination proteins are not necessary for maintenance. As
Taking Full Advantage of Host Homologous Recombination Factors
Because HPV is so dependent on the pathway, the virus has an array of tools for increasing its access to homologous recombination machinery. By binding and destabilizing the retinoblastoma protein (RB), HPV E7 increases homologous recombination protein abundance [29]. This is accomplished in part by raising RAD51 and BRCA1 stability. HPV E6 can cooperate with HPV E7 to further induce homologous recombination gene expression, increase the amount of RAD51, RPA70, BRCA1 and BRCA2 in cells [30].
Stressing the Cell to Gain Access
HPV amplification requires replication of typically quiescent cells. To satisfy this need, HPV E7 degrades Rb and RB-family proteins leading to increased E2F transcription and effectively preventing G1/S checkpoints [39]. By removing this constraint on cell proliferation, HPV E7 allows dysregulated growth that depletes nucleoside pools causing replication stress [40]. In response, the host cell undergoes multiple efforts to mitigate the replication stress. It becomes addicted to two
Hurting without Killing: HPV’s Repurposing of Homologous Recombination Factors Has Severe Consequences for Host Cells
Of course, HPV is not the only entity with an interest in how the cell responds to DSBs. Protecting genome fidelity is essential to the host cell’s survival. HPV infections further complicate the host’s mandate to protect its own DNA. The replication stress caused by the virus represents a notable challenge to cellular genome integrity [50]. As discussed in a preceding section, these responses are evidently unable to keep up as HPV oncogenes cause DSBs consistent with a failed or overwhelmed
Targeting HPV Oncogene Biology for Direct Translational Implications
HPV-associated tumors are addicted to HPV oncogene expression. Even though HeLa cells have been grown in laboratories around the world for decades, they remain sensitive to reduction of HPV E6 or E7 [57]. This is notable given that HPV oncogenes promote acquisition of the additional mutations required for transformation. If cells with a notably impaired DDR do not acquire the necessary mutations to become independent of HPV oncogene expression after nearly 70 years in culture, it is unlikely
Cutaneous HPV Infections Repress Homologous Recombination
Although we have focused exclusively on high-risk members of the α-Papillomavirus genus to this point, other human papillomaviruses have clinically relevant interactions with the homologous recombination pathway. Members of the β-Papillomavirus genus (β-HPVs) have a tropism for cutaneous rather than anogenital and oropharyngeal keratinocytes. β-HPVs augment nonmelanoma skin cancer development, especially in people with immunosuppression [70]. The World Health Organization and the International
Concluding Remarks
Nearly all of the death and disease caused by HPV infections can be avoided through vaccinations. Unfortunately, the antivaccine movement is a persistent scourge. In the developing world, fiscal and logistic restrictions represent additional barriers. Together, this has undermined the full benefits of HPV vaccination in most countries other than Australia [81]. For unvaccinated individuals, and people who are already infected with HPV, alternative therapies and improved biomarkers are still
Acknowledgments
I would like to thank Kansas State University’s Johnson Cancer Research Center, and particularly the Les Clow family, for their support. Further, Dr Koenrad VanDoerslaer was instrumental in creating the stylized image of the HPV genome. Thanks Vanni.
Glossary
- ATM
- an apical DNA repair kinase that typically responds to double-strand DNA breaks. It is activated during amplification and is necessary for the HPV lifecycle.
- ATR
- major DNA repair kinase. ATR most often responds to replication stress. HPV must activate ATR during amplification.
- BRCA1/2
- these two repair proteins are critical for homologous recombination and DNA crosslink repair. Both are induced by HPV oncogene expression, and BRCA1 is necessary for viral replication.
- DDR
- DNA damage repair;
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