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Viruses
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Viral Infection: A Threat for Genomic Stability in Host Cells
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Viral Infection: A Threat for Genomic Stability in Host Cells

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (23 December 2021) | Viewed by 21131

Special Issue Editors

Dr. Amélie Fradet-Turcotte

E-Mail Website
Guest Editor
Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Canada Research Chair in Molecular Virology and Genomic Instability, Oncology Division, CRCHU de Québec - Université Laval
Interests: DNA damage response; viral-host interaction; oncoviruses; carcinogenesis; chromatin signaling; response to chemo-/radiotherapy
Dr. Cary Moody

E-Mail Website
Guest Editor
Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Interests: HPV; DNA tumor viruses; chromatin; DNA repair; epigenetic regulation; genomic instability; cancer

Special Issue Information

Dear Colleagues,

Genomic instability is central to the acquisition of the biological capabilities that define cancer cells. Mutations in the proteins of the pathways that safeguard the stability of our genome are associated with cancer development, highlighting their role as tumor suppressors. 

Due to their limited coding capacity, viruses use different strategies to rewire the cellular environment of the host cell in order to stimulate their own replication and avoid clearance by innate immune response. Part of this process relies on the inhibition of cellular proteins that play dual roles in the antiviral response and the response to cellular DNA damage. Some viruses also directly hijack key proteins of these pathways to promote their own replication. In both cases, the inhibition of factors that safeguard genomic stability could be detrimental for the host cell. Indeed, recent genome-wide analyses revealed mutational signatures that are associated with defective DNA repair in cancers that are driven by oncogenic viruses. 

This Special Issue invites articles and reviews from experts in the field of oncogenic viruses and genomic stability to portray our current knowledge of the strategies used by viruses to manipulate pathways that maintain genomic stability in host cells. Articles and reviews addressing the impact of viral infections on the host genome are also welcome to highlight how viruses can facilitate the acquisition of mutations that promote carcinogenesis.  

Dr. Amélie Fradet-Turcotte
Dr. Cary Moody
Guest Editors

Manuscript Submission Information

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Published Papers (6 papers)

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Research

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22 pages, 6305 KiB  
Article
The Promotion of Genomic Instability in Human Fibroblasts by Adenovirus 12 Early Region 1B 55K Protein in the Absence of Viral Infection
by Tareq Abualfaraj, Nafiseh Chalabi Hagkarim, Robert Hollingworth, Laura Grange, Satpal Jhujh, Grant S. Stewart and Roger J. Grand
Viruses 2021, 13(12), 2444; https://doi.org/10.3390/v13122444 - 6 Dec 2021
Cited by 1 | Viewed by 2966
Abstract
The adenovirus 12 early region 1B55K (Ad12E1B55K) protein has long been known to cause non-random damage to chromosomes 1 and 17 in human cells. These sites, referred to as Ad12 modification sites, have marked similarities to classic fragile sites. In the present report [...] Read more.
The adenovirus 12 early region 1B55K (Ad12E1B55K) protein has long been known to cause non-random damage to chromosomes 1 and 17 in human cells. These sites, referred to as Ad12 modification sites, have marked similarities to classic fragile sites. In the present report we have investigated the effects of Ad12E1B55K on the cellular DNA damage response and on DNA replication, considering our increased understanding of the pathways involved. We have compared human skin fibroblasts expressing Ad12E1B55K (55K+HSF), but no other viral proteins, with the parental cells. Appreciable chromosomal damage was observed in 55K+HSFs compared to parental cells. Similarly, an increased number of micronuclei was observed in 55K+HSFs, both in cycling cells and after DNA damage. We compared DNA replication in the two cell populations; 55K+HSFs showed increased fork stalling and a decrease in fork speed. When replication stress was introduced with hydroxyurea the percentage of stalled forks and replication speeds were broadly similar, but efficiency of fork restart was significantly reduced in 55K+HSFs. After DNA damage, appreciably more foci were formed in 55K+HSFs up to 48 h post treatment. In addition, phosphorylation of ATM substrates was greater in Ad12E1B55K-expressing cells following DNA damage. Following DNA damage, 55K+HSFs showed an inability to arrest in cell cycle, probably due to the association of Ad12E1B55K with p53. To confirm that Ad12E1B55K was targeting components of the double-strand break repair pathways, co-immunoprecipitation experiments were performed which showed an association of the viral protein with ATM, MRE11, NBS1, DNA-PK, BLM, TOPBP1 and p53, as well as with components of the replisome, MCM3, MCM7, ORC1, DNA polymerase δ, TICRR and cdc45, which may account for some of the observed effects on DNA replication. We conclude that Ad12E1B55K impacts the cellular DNA damage response pathways and the replisome at multiple points through protein–protein interactions, causing genomic instability. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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Review

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14 pages, 1489 KiB  
Review
Merkel Cell Polyomavirus: Oncogenesis in a Stable Genome
by Mona M. Ahmed, Camille H. Cushman and James A. DeCaprio
Viruses 2022, 14(1), 58; https://doi.org/10.3390/v14010058 - 30 Dec 2021
Cited by 22 | Viewed by 3250
Abstract
Merkel cell polyomavirus (MCV) is the causative agent for the majority of Merkel cell carcinoma (MCC) cases. Polyomavirus-associated MCC (MCCP) is characterized by the integration of MCV DNA into the tumor genome and a low tumor mutational burden. In contrast, nonviral MCC (MCCN) [...] Read more.
Merkel cell polyomavirus (MCV) is the causative agent for the majority of Merkel cell carcinoma (MCC) cases. Polyomavirus-associated MCC (MCCP) is characterized by the integration of MCV DNA into the tumor genome and a low tumor mutational burden. In contrast, nonviral MCC (MCCN) is characterized by a high tumor mutational burden induced by UV damage. Since the discovery of MCV, much work in the field has focused on understanding the molecular mechanisms of oncogenesis driven by the MCV tumor (T) antigens. Here, we review our current understanding of how the activities of large T (LT) and small T (ST) promote MCC oncogenesis in the absence of genomic instability. We highlight how both LT and ST inhibit tumor suppressors to evade growth suppression, an important cancer hallmark. We discuss ST interactions with cellular proteins, with an emphasis on those that contribute to sustaining proliferative signaling. Finally, we examine active areas of research into open questions in the field, including the origin of MCC and mechanisms of viral integration. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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11 pages, 708 KiB  
Review
Genomic Signatures in HPV-Associated Tumors
by Suleman S. Hussain, Devon Lundine, Jonathan E. Leeman and Daniel S. Higginson
Viruses 2021, 13(10), 1998; https://doi.org/10.3390/v13101998 - 5 Oct 2021
Cited by 15 | Viewed by 3572
Abstract
Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human papillomaviruses (HPV) E6 and E7 oncoproteins mediate degradation of the cell cycle regulators p53 and Rb, which are [...] Read more.
Papillomaviruses dysregulate the G1/S cell cycle transition in order to promote DNA synthesis in S phase, which is a requirement for viral replication. The human papillomaviruses (HPV) E6 and E7 oncoproteins mediate degradation of the cell cycle regulators p53 and Rb, which are two of the most universally disrupted tumor-suppressor genes in all of cancer. The G1/S checkpoint is activated in normal cells to allow sufficient time for DNA repair in G1 before proceeding to replicate DNA and risk propagating unrepaired errors. The TP53 pathway suppresses a variety of such errors, including translocation, copy number alterations, and aneuploidy, which are thus found in HPV-associated tumors similarly to HPV-negative tumors with other mechanisms of TP53 disruption. However, E6 and E7 maintain a variety of other virus–host interactions that directly disrupt a growing list of other DNA repair and chromatin remodeling factors, implying HPV-specific repair deficiencies. In addition, HPV-associated squamous cell carcinomas tumors clinically respond differently to DNA damaging agents compared to their HPV negative counterparts. The focus of this review is to integrate three categories of observations: (1) pre-clinical understanding as to the effect of HPV on DNA repair, (2) genomic signatures of DNA repair in HPV-associated tumor genomes, and (3) clinical responses of HPV-associated tumors to DNA damaging agents. The goals are to try to explain why HPV-associated tumors respond so well to DNA damaging agents, identify missing pieces, and suggest clinical strategies could be used to further improve treatment of these cancers. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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16 pages, 1920 KiB  
Review
Dangerous Liaisons: Long-Term Replication with an Extrachromosomal HPV Genome
by Alix Warburton, Ashley N. Della Fera and Alison A. McBride
Viruses 2021, 13(9), 1846; https://doi.org/10.3390/v13091846 - 16 Sep 2021
Cited by 15 | Viewed by 3597
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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13 pages, 1050 KiB  
Review
Genomic Instability and DNA Damage Repair Pathways Induced by Human Papillomaviruses
by Takeyuki Kono and Laimonis Laimins
Viruses 2021, 13(9), 1821; https://doi.org/10.3390/v13091821 - 14 Sep 2021
Cited by 6 | Viewed by 3598
Abstract
Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway [...] Read more.
Human papillomaviruses (HPV) are the causative agents of cervical and other anogenital cancers as well as those of the oropharynx. HPV proteins activate host DNA damage repair factors to promote their viral life cycle in stratified epithelia. Activation of both the ATR pathway and the ATM pathway are essential for viral replication and differentiation-dependent genome amplification. These pathways are also important for maintaining host genomic integrity and their dysregulation or mutation is often seen in human cancers. The APOBEC3 family of cytidine deaminases are innate immune factors that are increased in HPV positive cells leading to the accumulation of TpC mutations in cellular DNAs that contribute to malignant progression. The activation of DNA damage repair factors may corelate with expression of APOBEC3 in HPV positive cells. These pathways may actively drive tumor development implicating/suggesting DNA damage repair factors and APOBEC3 as possible therapeutic targets. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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15 pages, 1563 KiB  
Review
Beta-Genus Human Papillomavirus 8 E6 Destabilizes the Host Genome by Promoting p300 Degradation
by Dalton Dacus and Nicholas A. Wallace
Viruses 2021, 13(8), 1662; https://doi.org/10.3390/v13081662 - 21 Aug 2021
Cited by 10 | Viewed by 2813
Abstract
The beta genus of human papillomaviruses infects cutaneous keratinocytes. Their replication depends on actively proliferating cells and, thus, they conflict with the cellular response to the DNA damage frequently encountered by these cells. This review focus on one of these viruses (HPV8) that [...] Read more.
The beta genus of human papillomaviruses infects cutaneous keratinocytes. Their replication depends on actively proliferating cells and, thus, they conflict with the cellular response to the DNA damage frequently encountered by these cells. This review focus on one of these viruses (HPV8) that counters the cellular response to damaged DNA and mitotic errors by expressing a protein (HPV8 E6) that destabilizes a histone acetyltransferase, p300. The loss of p300 results in broad dysregulation of cell signaling that decreases genome stability. In addition to discussing phenotypes caused by p300 destabilization, the review contains a discussion of the extent to which E6 from other β-HPVs destabilizes p300, and provides a discussion on dissecting HPV8 E6 biology using mutants. Full article
(This article belongs to the Special Issue Viral Infection: A Threat for Genomic Stability in Host Cells)
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