Foreign DNA in Mammalian Cells and Organisms

Doerfler, Walter; Fechteler, Katja; Heller, Hilde; Kämmer, Christina; Knoblauch, Margit; Koetsier, Paul A.; Orend, Gertraud; Schröer, Jörg; Schubbert, Rainer

doi:10.1007/978-3-642-61460-6_13

Cited by 18 publications

(24 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[21][22][23] The resulting chromatin changes constitute a major molecular pathway that regulates cellular gene expression during embryogenesis and differentiation. In the biology of most viruses DNA methylation does not appear to play a role, but previous studies from our group [24][25][26][27][28] and others [34][35][36] have shown that HPV-16 and 18 are among those few viruses that are strongly affected by this mechanism.…”

Section: Discussionmentioning

confidence: 95%

“…26,36 This phenomenon, which mostly affects the viral enhancer and occurs at very low levels of HPV DNA concentration, is unfortunately not yet well understood because of the difficulties to study these viruses in cell culture. The research presented here does not attempt to address DNA methylation during the normal viral biology.…”

Section: Discussionmentioning

confidence: 99%

“…37 As a consequence, a combination of high HPV DNA concentrations in a clinical sample combined with hypermethylation of L1, the enhancer and promoter has become a useful test to detect recombination, and thereby characterize established malignancies and identify mixed cell populations with subpopulations that progress toward malignancy. [26][27][28]35,36 Here we documented that HPV-16 genomes in 10 out of 12 carcinomas of the oral cavity were altered by DNA methylation in a manner typical of carcinomas and high-grade lesions of the cervix and the anus, suggesting that HPV-16 genomes are chromosomally integrated in oral malignancies and affect the host cells in a similar manner as in anogenital malignancies. It should also be noted that certain patterns, e.g.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Balderas-Loaeza

Anaya‐Saavedra

Ramírez‐Amador

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

Infection with human papillomavirus-16 (HPV-16) is the cause of most anogenital carcinomas. This virus is also detected in about 20% of all head and neck squamous cell carcinomas. While there is strong evidence for a causal etiological role in the case of tonsillar carcinomas, causal association with malignant lesions of the oral cavity is not yet conclusive. Our previous investigations of HPV-16 DNA methylation in anogenital sites have identified hypermethylation of the L1 gene and part of the long control region in many malignant lesions, but rarely in asymptomatic infections and low-grade precancerous lesions. Here, we report hypermethylation of this diagnostically important segment of the viral DNA in 10 out of 12 HPV-16 positive oral carcinomas from Mexican patients. These data indicate epigenetic changes of HPV-16 in oral carcinomas similar to those in anogenital carcinomas, suggesting carcinogenic processes under the influence of HPV-16 in most if not all of these oral malignant lesions. ' 2007 Wiley-Liss, Inc.Key words: papillomavirus; carcinoma; head and neck cancer; oral cavity; DNA methylation; DNA recombination; etiology; progression; Infection with human papillomaviruses (HPVs), notably with high-risk HPV types such as HPV-16 and 18, is a necessary step in the etiology of anogenital cancers, specifically carcinoma of the cervix uteri. This notion is based on epidemiological research that identified a high relative risk of carcinogenic progression associated with high-risk HPV infection, DNA diagnosis that confirmed the presence and transcription of HPV genomes in all cervical carcinomas, and the study of HPV oncoproteins that catalyze a variety of molecular mechanisms that convert normal into malignant cells. [1][2][3][4][5][6] In case of head and neck squamous cell carcinomas (HNSCCs), an HPV dependent etiology is not as consistently confirmed as in anogenital cancers. Approximately 80% of all HNSCCs do not contain HPV genomes, and must therefore originate from HPV independent etiological processes, likely including mutational events triggered by tobacco and alcohol consumption. However, there is extensive evidence that a proportion of all HNSCCs contain DNA of high-risk HPV types. 7-14 Among head and neck sites, squamous cell carcinomas of the tonsils have the strongest statistical support for an HPV dependent etiology. 9,[15][16][17] There is less strength and consistency for a linkage between HPV infection and carcinogenesis at sites of the oral mucosa such as tongue, palate, floor of mouth and gingiva. Nevertheless, epidemiological studies have established statistical evidence for a causal association of HPVs and malignancies even for these oral sites. 9,16 In addition, analysis of some HPV containing oral carcinomas revealed recombination between HPV genomes and cellular DNA as well as HPV oncogene expression, [10][11][12][13][18][19][20] properties that are generally viewed as support of carcinogenic processes under the influence of HPVs. On the basis of these observations one must conclude ...

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Balderas-Loaeza

Anaya‐Saavedra

Ramírez‐Amador

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Methylation of exogenous DNA (including viral DNA) that is integrated into the human genome has been studied over the past decade (Doerfler et al 2001). Within the human genome, cytosine methylation in CpG dinucleotides (CpG sites), which cluster into islands associated with transcriptional promoters, is an important mechanism for regulating gene expression.…”

mentioning

confidence: 99%

DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences

et al. 2015

View full text Add to dashboard Cite

Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis.

show abstract

“…Moreover, it was found earlier that genomic DNA fragments originating presumably from cell apoptosis are always present in tissue fluids and blood plasma in form of oligonucleosomes, chromatin-like nano-scale particles. 18 As with oligonucleotides, nano-DNAs of at least 1,000 bp can spontaneously penetrate biological barriers and cell envelopes via a receptor-mediated mechanism and be delivered into cell nuclei, even from the small intestines, [19][20][21][22] which may make it possible to solve the delivery issue and use nano-DNAs in vivo.…”

Section: Introductionmentioning

confidence: 99%

Natural Human Gene Correction by Small Extracellular Genomic DNA Fragments

Yakubov¹,

Рогачев²,

Likhacheva³

et al. 2007

Cell Cycle

View full text Add to dashboard Cite

Classical gene targeting employs natural homologous recombination for a gene correction using a specially designed and artificially delivered DNA construct but the method is very inefficient. On the other hand, small DNA fragments in the form of tiny chromatin-like particles naturally present in blood plasma can spontaneously penetrate into human cells and cell nuclei. We hypothesized that these natural DNA nanoparticles with recombinagenic free ends might be effective agents for gene replacement therapy. We demonstrate that a mixture of small fragments of total human chromatin from nonmutant cells added to a culture medium without transfection agents efficiently repaired a 47 base pair deletion in the CASP3 gene in 30% of treated human MCF7 breast cancer cells, as shown by restoration of caspase-3 apoptotic function and CASP3 DNA and mRNA structure. Such an innate gene replacement mechanism might function naturally in an organism using its own apoptotic DNA fragments. This mechanism might enable human cancer cell phenotype normalization in the presence of excess normal cells.Gene targeting (GT) modifies a gene in its chromosomal location, preserving existing mechanisms to regulate its function in cells, and thereby holds great promise as a medical treatment strategy. 1-3 GT employs endogenous homologous recombination (HR) and homologous sequences contained in targeting DNA constructs for modification of a target sequence in genomic DNA. The GT used in reverse genetics studies requires artificial transfection, sophisticated targeting vectors, and drug-based selection to overcome the extremely low efficiency of the method, making it impractical for in vivo or therapeutic use. 2 Earlier it was found that the GT yield increases up to 100-fold by increasing the homology length in a donor consruct above 10 kbp, but still remains insufficient for in vivo applications. 4 However, it was also shown that the homology length required for HR in mammals is only around 100-400 bp, 5-7 suggesting that small DNA constructs might be effective. Indeed, the surprisingly high 1-10% repair efficiency demonstrated by a GT method called small fragment homologous replacement (SFHR) using DNA constructs a few hundred bp in length 8 might indicate that the small size of those constructs is favorable for GT. Free DNA ends, resulting from cutting of either targeting plasmid or target DNA in the region of common homology, are highly recombinagenic, enhancing HR locally in both yeast 9 and mammalian 10,11 cells. Recently this approach was used for repairing a point mutation using simultaneous transfection of a plasmid containing a short homologous donor DNA (1.5 kbp) and a construct expressing artificial zinc-finger nucleases specifically inducing DSBs in proximity to the mutation, which led to 20% efficiency of the target repair. 12 Another GT strategy called "ends-out" or gene replacement allows repair of extended genetic mutations without generating potentially mutagenic DSBs by using recombinant linear DNA in which the two ends ...

show abstract

Foreign DNA in Mammalian Cells and Organisms

Cited by 18 publications

References 11 publications

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

Human papillomavirus‐16 DNA methylation patterns support a causal association of the virus with oral squamous cell carcinomas

DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences

Natural Human Gene Correction by Small Extracellular Genomic DNA Fragments

Contact Info

Product

Resources

About