-
Cold Spring Harbor Perspectives in... Aug 2021Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and... (Review)
Review
Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and therefore transverse the nuclear envelope barrier through the nuclear pore complex. Viral genomes then become chromatinized either in their episomal form or upon integration into the host genome. Interactions with host DNA, transcription factors or nuclear bodies mediate their replication. Often interfering with nuclear functions, viruses use nuclear architecture to ensure persistent infections. Discovering these multiple modes of replication and persistence served in unraveling many important nuclear processes, such as nuclear trafficking, transcription, and splicing. Here, by using examples of DNA and RNA viral families, we portray the nucleus with the virus inside.
Topics: Animals; Cell Nucleus; DNA Viruses; Gene Expression Regulation, Viral; Humans; RNA Viruses; Virus Integration
PubMed: 33753405
DOI: 10.1101/cshperspect.a039446 -
Frontiers in Cellular and Infection... 2022The incidence of cancer is high worldwide, and biological factors such as viruses and bacteria play an important role in the occurrence of cancer. , , and other... (Review)
Review
The incidence of cancer is high worldwide, and biological factors such as viruses and bacteria play an important role in the occurrence of cancer. , , and other organisms have been identified as carcinogens. Cancer is a disease driven by the accumulation of genome changes. Viruses can directly cause cancer by changing the genetic composition of the human body, such as cervical cancer caused by DNA integration and liver cancer caused by DNA integration. Recently, bacterial DNA has been found around cancers such as pancreatic cancer, breast cancer and colorectal cancer, and the idea that bacterial genes can also be integrated into the human genome has become a hot topic. In the present paper, we reviewed the latest phenomenon and specific integration mechanism of bacterial DNA into the human genome. Based on these findings, we also suggest three sources of bacterial DNA in cancers: bacterial DNA around human tissues, free bacterial DNA in bacteremia or sepsis, and endogenous bacterial DNA in the human genome. Clarifying the theory that bacterial DNA integrates into the human genome can provide a new perspective for cancer prevention and treatment.
Topics: Female; Humans; DNA, Bacterial; Virus Integration; Carcinogenesis; Uterine Cervical Neoplasms; Genome, Human; DNA, Viral
PubMed: 36310856
DOI: 10.3389/fcimb.2022.996778 -
Viruses Nov 2021Retroviral infection delivers an RNA genome into the cytoplasm that serves as the template for the synthesis of a linear double-stranded DNA copy by the viral reverse... (Review)
Review
Retroviral infection delivers an RNA genome into the cytoplasm that serves as the template for the synthesis of a linear double-stranded DNA copy by the viral reverse transcriptase. Within the nucleus this linear DNA gives rise to extrachromosomal circular forms, and in a key step of the life cycle is inserted into the host genome to form the integrated provirus. The unintegrated DNA forms, like those of DNAs entering cells by other means, are rapidly loaded with nucleosomes and heavily silenced by epigenetic histone modifications. This review summarizes our present understanding of the silencing machinery for the DNAs of the mouse leukemia viruses and human immunodeficiency virus type 1. We consider the potential impact of the silencing on virus replication, on the sensing of the virus by the innate immune system, and on the formation of latent proviruses. We also speculate on the changeover to high expression from the integrated proviruses in permissive cell types, and briefly consider the silencing of proviruses even after integration in embryonic stem cells and other developmentally primitive cell types.
Topics: Animals; DNA, Viral; Gene Silencing; HIV-1; Histone Code; Humans; Leukemia Virus, Murine; Proviruses; Retroviridae; Transcription, Genetic; Virus Integration; Virus Replication
PubMed: 34835055
DOI: 10.3390/v13112248 -
Viruses Jan 2021Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of... (Review)
Review
Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear environment where the chromosomes reside. Retroviral integration is non-random, with different types of virus-host interactions impacting where in the host chromatin integration takes place. Lentiviruses such as HIV efficiently infect interphase cells because their RTCs have evolved to usurp cellular nuclear import transport mechanisms, and research over the past decade has revealed specific interactions between the HIV capsid protein and nucleoporin (Nup) proteins such as Nup358 and Nup153. The interaction of HIV capsid with cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular cleavage and polyadenylation complex, helps to dictate nuclear import as well as post-nuclear RTC invasion. In the absence of the capsid-CPSF6 interaction, RTCs are precluded from reaching nuclear speckles and gene-rich regions of chromatin known as speckle-associated domains, and instead mis-target lamina-associated domains out at the nuclear periphery. Highlighting this area of research, small molecules that inhibit capsid-host interactions important for integration site targeting are highly potent antiviral compounds.
Topics: Active Transport, Cell Nucleus; Capsid; Capsid Proteins; Chromatin; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Nuclear Pore Complex Proteins; Protein Binding; Structure-Activity Relationship; Virus Integration
PubMed: 33477441
DOI: 10.3390/v13010125 -
Gut Jun 2024Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on...
OBJECTIVE
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further.
DESIGN
Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice.
RESULTS
These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (), 6q, 8p, 16q, 9p (), 17p () and 13q (), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the and amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials.
CONCLUSION
HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.
Topics: Carcinoma, Hepatocellular; Liver Neoplasms; Hepatitis B virus; Humans; Virus Integration; Animals; Mice; Male; Middle Aged; Female; Adult; Whole Genome Sequencing; DNA Copy Number Variations; Aged
PubMed: 38395437
DOI: 10.1136/gutjnl-2023-330414 -
MBio Jan 2024HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell.... (Review)
Review
HIV-1 capsid protein (CA)-independently or by recruiting host factors-mediates several key steps of virus replication in the cytoplasm and nucleus of the target cell. Research in the recent years have established that CA is multifunctional and genetically fragile of all the HIV-1 proteins. Accordingly, CA has emerged as a validated and high priority therapeutic target, and the first CA-targeting antiviral drug was recently approved for treating multi-drug resistant HIV-1 infection. However, development of next generation CA inhibitors depends on a better understanding of CA's known roles, as well as probing of CA's novel roles, in HIV-1 replication. In this timely review, we present an updated overview of the current state of our understanding of CA's multifunctional role in HIV-1 replication-with a special emphasis on CA's newfound post-nuclear roles, highlight the pressing knowledge gaps, and discuss directions for future research.
Topics: Humans; Capsid; Capsid Proteins; DNA, Viral; HIV-1; HIV Seropositivity; HIV Infections; Virus Replication; Virus Integration
PubMed: 38085100
DOI: 10.1128/mbio.00212-22 -
Proceedings of the National Academy of... May 2021Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after...
Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating viral-host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3' end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.
Topics: Animals; COVID-19; Chlorocebus aethiops; Genome, Viral; HEK293 Cells; Humans; RNA, Viral; SARS-CoV-2; Vero Cells; Virus Integration; Virus Replication
PubMed: 33958444
DOI: 10.1073/pnas.2105968118 -
Cancer Discovery Apr 2023The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous...
UNLABELLED
The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
SIGNIFICANCE
Long-read sequencing of HPV-positive cancers revealed "heterocateny," a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution. See related commentary by McBride and White, p. 814. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Human Papillomavirus Viruses; Papillomavirus Infections; Gene Rearrangement; Oropharyngeal Neoplasms; Clonal Evolution; Virus Integration; Papillomaviridae
PubMed: 36715691
DOI: 10.1158/2159-8290.CD-22-0900 -
Nature Communications Oct 2022Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput...
Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput HPV captured sequencing, whole-genome sequencing, whole-transcriptome sequencing, and OncoScan microarrays. HPV18 infections and integrations are commonly detected. Besides MYC family genes (37.9%), we identify SOX (8.4%), NR4A (6.3%), ANKRD (7.4%), and CEA (3.2%) family genes as HPV-integrated hotspots. We construct the genomic local haplotype around HPV-integrated sites, and find tandem duplications and amplified HPV long control regions (LCR). We propose three prominent HPV integration patterns: duplicating oncogenes (MYCN, MYC, and NR4A2), forming fusions (FGFR3-TACC3 and ANKRD12-NDUFV2), and activating genes (MYC) via the cis-regulations of viral LCRs. Moreover, focal CNA amplification peaks harbor canonical cancer genes including the HPV-integrated hotspots within MYC family, SOX2, and others. Our findings may provide potential molecular criteria for the accurate diagnosis and efficacious therapies for this lethal disease.
Topics: Alphapapillomavirus; Carcinoma, Small Cell; Female; Humans; Microtubule-Associated Proteins; N-Myc Proto-Oncogene Protein; Nuclear Proteins; Papillomaviridae; Papillomavirus Infections; Uterine Cervical Neoplasms; Virus Integration
PubMed: 36216793
DOI: 10.1038/s41467-022-33359-w -
Yi Chuan = Hereditas Mar 2021As the most abundant biological entities on earth, bacteriophages (phages) were considered as the antagonists of bacteria. With the rapid development of genomics and... (Review)
Review
As the most abundant biological entities on earth, bacteriophages (phages) were considered as the antagonists of bacteria. With the rapid development of genomics and molecular biology technologies, a subtle and complex relationship between phages and their host bacteria has been uncovered. Prophage refers to an intracellular form of a bacteriophage, which is usually integrated into the hereditary material of the host. Prophage is ubiquitously distributed in bacterial genomes. It reproduces when the host does and can affect important biological properties of their bacterial hosts, such as virulence, biofilm formation and host immunity. Interestingly, prophages were also involved in regulating the lysogeny-lytic state by "monitoring" the quorum sensing of bacteria. Recently, anti-CRISPR proteins encoded by prophages were found, which attracts a lot of attention. In this review, we summarized the prediction, distribution, classification and functions of prophages to lay a foundation for further studying interactions between phages and bacteria.
Topics: Bacteria; Bacteriophages; Genome, Bacterial; Lysogeny; Prophages
PubMed: 33724208
DOI: 10.16288/j.yczz.20-355