[Extrachromosomal DNA in the MRE 600 strain of Escherichia coli].
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DNA, Bacterial↗
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Modern biology of extrachromosomal DNA: A decade-long voyage of discovery.
Genomic instability is a hallmark of cancer and is a major driving force of tumorigenesis. A key manifestation of genomic instability is the formation of extrachromosomal DNAs (ecDNAs) - acentric, circular DNA molecules ranging from 50 kb to 5 Mb in size, distinct from chromosomes. Ontological studies have revealed that ecDNA serves as a carrier of oncogenes, immunoregulatory genes, and enhancers, capable of driving elevated transcription of its cargo genes and cancer heterogeneity, leading to rapid tumor evolution and therapy resistance. Although ecDNA was documented over half a century ago, the past decade has witnessed a surge in breakthrough discoveries about its biological functions. Here, we systematically review the modern biology of ecDNA uncovered over the last ten years, focusing on how discoveries during this pioneering stage have illuminated our understanding of ecDNA-driven transcription, heterogeneity, and cancer progression. Furthermore, we discuss ongoing efforts to target ecDNA as a novel approach to cancer therapy. This burgeoning field is entering a new phase, poised to reshape our knowledge of cancer biology and therapeutic strategies.
Humans↗
Extrachromosomal DNA-Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN-Amplified Cancers.
UNLABELLED: Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting high-risk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number-dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage-driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. SIGNIFICANCE: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related commentary by Korsah, p. 1979.
Humans↗
scAmp enables focal gene amplification analysis from single-cell data.
Oncogene amplification on extrachromosomal DNA is a common driver of tumor progression and is associated with acquired drug resistance and poor patient survival. While bulk whole genome sequencing studies have revealed the landscape of genes amplified on extrachromosomal DNA in tumors, it remains challenging to study the subclonal heterogeneity and functional (e.g., transcriptomic) consequences of extrachromosomal DNA on tumors. To address this, we introduce scAmp: a probabilistic algorithm for detecting and analyzing extrachromosomal DNA from single-cell datasets. Using well-characterized cell lines, we demonstrate that scAmp has improved specificity over bulk genome sequencing in predicting extrachromosomal DNA status and can resolve the status of chromosomal amplifications that were historically extrachromosomal. We further showcase scAmp by analyzing 73 patient tumors profiled with single-cell assay for transposase-accessible chromatin by sequencing, where we characterize the subclonal evolution of subclones with extrachromosomal DNA and identify the effect of these amplifications on the chromatin accessibility landscape of cancer cells. Finally, we provide proof-of-concept analyses that scAmp aids in the detection of extrachromosomal DNA from clinical histopathology assays. Together, we anticipate that scAmp will broadly enable further studies - both retrospective and prospective - that dissect critical questions of how extrachromosomal DNAs affect cancer cells and the tumors in which they reside.
Humans↗
Absence of rDNA amplification in the uninucleolate oocyte of the cockroach Blattella germanica (Oorthoptera: Blattidae).
Amplification of the genes coding for ribosomal RNA oocurs in the oocytes of a wide variety of organisms. In oocytes of various species of crickets (Orthoptera: Gryllidae) the amplified DNA is contained in a large extrachromosomal DNA body. Multiple nucleoli form about the periphery of the DNA body during the diplotene stage of meiosis I. In contrast to the general pattern of orthopteran oocytes, oocytes of the cockroach Blattella germanica demonstrate a single large nucleolus instead of many nucleoli. In order to determine whether the genes coding for rRNA are amplified in the oocytes of B. germanica, the relative amount of rDNA in oocytes was compared with the rDNA content of spermatocytes and somatic cells. An extrachromosomal DNA body similar to that present in crickets is not present in B. germanica. A satellite DNA band which contains nucleotide sequences complementary to rRNA accounts for approximately 3-5% of the total DNA in somatic and in male and female gametogenic tissues. Female cells contain approximately twice as much rDNA as do male cells. An XX-XO sex-determining mechanism is operative in B. germanica. In situ hybridization with rRNA indicates that the nucleolar organizer is located on one end of the X chromosome and that oocytes do not contain more than twice the amount of rDNA found in spermato cytes. The data indicate that rDNA is not amplified in the uninucleolate oocyte of B germanica.
Animals↗
Restriction endonuclease mapping of unintegrated proviral DNA of Snyder-Theilen feline sarcoma virus: localization of sarcoma-specific sequences.
Extrachromosomal DNA purified from mink cells acutely infected with the Snyder-Theilen strain of feline sarcoma virus (FeSV) was digested with restriction endonucleases, and the DNA fragments were electrophoretically separated, transferred to a solid substrate, and hybridized with radiolabeled DNA transcripts complementary to different portions of the FeSV RNA genome. Major DNA species 8.4 and 5.0 kilobase pairs (kbp) long represent the linear, unintegrated proviruses of Snyder-Theilen feline leukemia virus and FeSV, respectively. Transfection experiments performed with electroeluted DNAs showed that the 8.4-kbp form led to the production of replicating nontransforming virus in mink and cat cells; in contrast, the 5.0-kbp DNA produced helper virus-independent foci of transformation in mouse NIH/3T3 cells and helper virus-dependent foci in mink cells at an efficiency comparable to that obtained with unfractionated extrachromosomal DNA. Sites of restriction endonuclease cleavage for six enzymes were oriented with respect to one another within the FeSV provirus. EcoRI recognized cleavage sites at 0.3 to 0.4 kbp from each terminus of FeSV DNA, reducing the 5.0-kbp DNA to molecules 4.3 kbp long; this enzyme excised a large internal proviral DNA fragment of corresponding size from the DNA of FeSV-transformed mink nonproducer cells. By using DNA transcripts complementary to different portions of the FeSV genome, sarcoma-specific sequences (the FeSV src gene) were positioned within 2.1 and 3.4 kbp from the 5' end of the proviral DNA with respect to the viral RNA genome. The src gene is flanked at both ends by sequences shared in common with feline leukemia virus. The localization of src sequences to this region suggests that a portion of an FeSV polyprotein which contains feline oncornavirus-associated cell membrane antigen (FOCMA-S) is the major product of this gene.
Animals↗
Hypertranscription caused by p53 deficiency triggers nucleotide insufficiency that induces replication stress and genomic instability.
p53 plays a central role in the DNA damage response, inducing repair, cell-cycle arrest or apoptosis. Its loss is associated with replication stress and genomic instability. While several underlying mechanisms were suggested, the primary triggers of catastrophic genomic events like chromothripsis, a known driver of tumorigenesis linked with p53 loss, are still unclear. Using p53-depleted epithelial cells and fibroblasts, as well as patient-derived fibroblasts with germline p53 variants that spontaneously undergo chromothripsis, we found that p53 loss causes hypertranscription and increased nucleotide consumption. The resulting nucleotide shortage induces replication stress, causing telomere dysfunction, micronuclei formation, and chromothripsis. These effects were rescued by nucleoside supplementation or normalization of transcription levels, demonstrating a causal link between transcriptional activity, nucleotide availability, and genome stability. Emerging chromothriptic clones displayed restored DNA replication, telomere stabilization, and extrachromosomal DNA, suggesting key features that support clonal selection. We identify nucleotide pool homeostasis as a critical p53 function that suppresses replication stress, prevents chromothripsis, and protects against early tumorigenesis.
Genomic Instability↗
Whole-genome sequencing reveals hidden antimicrobial resistance genes in phenotypically susceptible probiotic candidate lactic acid bacteria.
Phenotypic assays commonly used to evaluate probiotic safety may fail to detect clinically relevant antimicrobial resistance (AMR), potentially allowing genetically concerning strains to appear acceptable based on MIC testing alone. To explore this issue, we applied whole-genome sequencing (WGS) to three lactic acid bacteria (LAB) isolates previously identified as probiotic candidates based on acid and bile tolerance, antagonism against enteric pathogens, and biofilm formation in vitro: Lactiplantibacillus plantarum L25F and L22F (from pigs) and Ligilactobacillus salivarius AF2319 (from a chicken). Genome annotation identified extensive repertoires of probiotic-associated genes (46-47 per strain) linked to stress tolerance, adhesion, immunomodulation, and quorum sensing, supporting functional potential. The two L. plantarum strains exhibited broader predicted metabolic capacities than L. salivarius AF2319. However, genomic analysis revealed acquired AMR genes with complex genotype-phenotype relationships not fully apparent from phenotypic testing. The L. plantarum strains harbored lnu(A) (99.79% identity) on extrachromosomal DNA, conferring the L-phenotype (lincomycin resistance, clindamycin susceptibility); clindamycin MICs (1 mg/L) were concordant with this genotype, though lincomycin MICs were not determined. L. salivarius AF2319 carried tet(M), tet(L), and erm(C) (99.48%, 99.49%, and 99.45% identity by ResFinder, respectively) on extrachromosomal DNA; notably, the erythromycin MIC (1 mg/L) was precisely at the EFSA breakpoint (≤ 1 mg/L), representing borderline genotype-phenotype discordance potentially due to silent gene expression. Under current EFSA QPS criteria, these acquired ARGs would preclude all three strains from approval as probiotic feed additives despite favorable functional profiles, underscoring the indispensable role of WGS-based AMR gene detection in modern probiotic safety evaluation.
Probiotics↗
[Nuclear structures in the telotrophic ovarioles of nocturnal ground beetles (Tenebrionidae, Polyphaga). III. The oocyte nucleus. Electron microscopic data].
The fine structural organization of nuclei was studied in the growing oocytes of Blaps lethifera, B. mortisaga and Gnaptor spinimanus. In the beginning of diplotene the nuclei contain primary fibrillar nucleoli and numerous electron dense globules dispersed all over the nucleus; the loose chromosome material (lampbrush chromosomes) is distributed all over the nucleus. With the oocyte growth the chromosomes are spiralized and join into the karyosphere. A capsule of fibrous material forms around the karyosphere. The karyosphere nucleoli appear on the chromosomes and, then, move to the capsule region and outside its limits, to the nuclear envelope. They are fibrillar and non-active with respect to RNA synthesis. The fibrous material of the capsule is represented by strands which consist of bundles of cross-striated filaments. These latter contact directly with the chromosomes in the karyosphere and with the surface of the karyosphere nucleoli. The fibrillar-granular bodies are distributed along the strands in the capsule; they contain both RNA and DNA. The nature of extrachromosomal DNA in the karyosphere capsule and its participation in the formation of the capsule material are discussed. A suggestion is put forward on the similarity of the capsule strands with the modified central elements of synaptinemal complex.
Animals↗
Identification of Genome-Wide Chromatin Structural Aberration in Cancer by Hi-C Analysis.
Aberrant three-dimensional genome organization is a hallmark of cancer, often driving oncogene activation through mechanisms such as enhancer hijacking. High-throughput chromosome conformation capture (Hi-C) maps these interactions on a genome-wide scale. Unlike earlier dilution-based methods, in situ Hi-C performs proximity ligation within intact nuclei, minimizing random ligation noise and enabling fine-scale structure detection. This chapter describes an optimized in situ Hi-C protocol tailored for cancer cell lines using MboI digestion and biotin-mediated pull-down to generate high-complexity libraries. We further outline a computational workflow that extends beyond standard topological mapping of compartments and topologically associating domains to identify cancer-specific aberrations. Specifically, we focus on detecting chromosomal rearrangements (structural variants) and characterizing the distinct circular topology of extrachromosomal DNA. This integrated experimental and analytical framework provides the necessary tools to dissect the spatial dysregulation underlying tumor evolution.
Humans↗
The organisation of genes for transfer RNA and ribosomal RNA in amoebae and plasmodia of Physarum polycephalum.
1. Using hybridisation techniques nuclei from both amoebae and plasmodia of Physarum polycephalum were found to contain 275 genes each coding for 5.8-S, 19-S and 26-S rRNA, 685 genes for 5-S rRNA and 1050 genes for tRNA. 2. Hybridisation of these RNA species to both amoebal and plasmodial DNA fractionated on CsCl gradients reveal that the 5.8-S, 19-S and 26-S rRNA genes are located at a satellite position (formula: see text) with respect to the main band of DNA, whereas 4-S RNA genes are located exclusively in the main band of DNA (formula: see text). 3. This result was confirmed by demonstrating that only the 5.8-S, 19-S and 26-S rRNA species hybridise to purified plasmodial ribosomal DNA. 4. The 19-S and 26-S rRNA genes of amoebae are located on extrachromosomal DNA molecules of a discrete size (Mr = 38 X 10(6)) with identical properties to plasmodial ribosomal DNA.
Cell Nucleus↗
Genomic instability, postoperative recurrence and therapeutic vulnerabilities in resectable non‑small cell lung cancer (Review).
Resectable non‑small cell lung cancer (NSCLC) is managed largely according to anatomical stage, pathological risk and actionable driver alterations, yet these factors do not fully explain postoperative recurrence. Genomic instability may contribute to recurrence by promoting clonal diversification, intratumoral heterogeneity, occult dissemination, persistence of residual tumor cells, and immune escape. In the present review, chromosomal instability (CIN), copy‑number complexity, whole‑genome doubling, DNA repair defects, replication stress, and extrachromosomal DNA (ecDNA) were critically evaluated using a three‑axis translational framework encompassing biological consequences, potential clinical roles, and strength of evidence. Current evidence suggests that clonal diversity and copy‑number complexity have the clearest near‑term prognostic rationale. By contrast, CIN and whole‑genome doubling are supported more strongly by evolutionary and mechanistic rather than prospective clinical evidence. Defects in DNA repair, replication stress, and ecDNA represent potential therapeutic vulnerabilities, but their clinical relevance remains to be established. To date, no treatment‑predictive biomarkers based on genomic instability have been identified for resectable NSCLC. Direct clinical evidence linking any specific genomic instability feature to the presence or longitudinal dynamics of postoperative molecular residual disease (MRD) remains limited. Postoperative circulating tumor DNA‑defined MRD provides prognostic information more directly related to residual disease but remains assay‑dependent and should not be considered a genomic‑instability phenotype. Therefore, features of genomic instability should remain investigational and should not replace established clinical, pathological, or molecular decision‑making. Their near‑term value lies in refining biological risk models and generating testable hypotheses for biomarker‑defined perioperative trials.
Humans↗
CRISPR/Cas- and Argonaute-Based In Vivo Nucleic-Acid Imaging Technologies: Strategies, Challenges, and Perspectives.
Live-cell monitoring of sequence-specific nucleic acids is essential to understanding genome organization, RNA regulation, and disease progression. Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) and Argonaute (Ago) systems provide programmable, guide-directed recognition of DNA or RNA and are increasingly used as platforms for in vivo bioimaging. This review summarizes the structural and mechanistic features of representative CRISPR and Ago effectors and discusses design strategies for sensitive, specific, and multiplexed imaging of genomic loci, extrachromosomal DNA, and endogenous RNA in living cells. We compare the analytical performance and limitations of CRISPR- and Ago-based imaging, with particular emphasis on the major technical and biological challenges affecting their accuracy, applicability, and reliability. Finally, this review offers insights into developing high-resolution and user-friendly bioimaging platforms for fundamental biology and future translational applications.
CRISPR↗
Characterisation of whole-blood extrachromosomal circular DNAs in Kawasaki disease complicated by coronary artery aneurysm.
BACKGROUND: Extrachromosomal circular DNAs are critical regulators of stress responses, immunity, and inflammation pathways. However, their role and underlying mechanisms in Kawasaki disease complicated by coronary artery aneurysm remain poorly understood. METHODS: Whole blood samples from six children with Kawasaki disease, including three with coronary artery aneurysm group and three without coronary artery aneurysm (control group), were subjected to extrachromosomal circular DNA sequencing. Putative extrachromosomal circular DNAs were identified using Circle-Map. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on genes associated with upregulated extrachromosomal circular DNAs, and an exploratory immune-signature profiling was performed using the single-sample gene set enrichment analysis algorithm. RESULTS: We identified 4,790 differential extrachromosomal circular DNAs between the coronary artery aneurysm and control groups, of which 4,789 were upregulated in the CAA group. The extrachromosomal circular DNAs in the coronary artery aneurysm group were more concentrated and shorter in length than those in the control group. Upregulated extrachromosomal circular DNAs were mainly derived from autosomes, particularly chromosomes 3, 4, and 7. Functional enrichment analysis indicated that genes associated with upregulated extrachromosomal circular DNAs were mainly involved in response to stimulus-related terms and pathways, including chemokine signalling, cGMP-PKG signalling, and calcium signalling. Immune-signature analysis suggested that the coronary artery aneurysm group exhibited more specific immune responses, whereas the control group tended towards broader immune regulatory processes. CONCLUSIONS: Coronary artery aneurysm and control groups exhibited distinct extrachromosomal circular DNA profiles. These findings suggest that extrachromosomal circular DNA alterations are associated with coronary artery aneurysm in Kawasaki disease and may provide new insights into the molecular features underlying this condition.
Coronary artery aneurysm↗
Plasmid interactions in Staphylococcus aureus: nonadditivity of compatible plasmid DNA pools.
Six different Staphylococcus aureus plasmids have been examined for compatibility relationships and their intracellular DNA pools have been measured singly and in various combinations. All six were mutually compatible, but contrary to expectation, their intracellular DNA pools were not additive; instead, there appeared to be a maximum level of extrachromosomal DNA that could be supported by the cell, and the plasmids studied approached this level individually as well as in varous combinations. One exception was encountered: a plasmid encoding kanamycin/neomycin resistance was present in a small but constant number of copies regardless of the presence of other plasmids.
DNA, Bacterial↗
Replication of each copy of the yeast 2 micron DNA plasmid occurs during the S phase.
Saccharomyces cerevisiae contains 50-100 copies per cell of a circular plasmid called 2 micron DNA. Replication of this DNA was studied in two ways. The distribution of replication events among 2 micron DNA molecules was examined by density transfer experiments with asynchronous cultures. The data show that 2 micron DNA replication is similar to chromosomal DNA replication: essentially all 2 micron duplexes were of hybrid density at one cell doubling after the density transfer, with the majority having one fully dense strand and one fully light strand. The results show that replication of 2 micron DNA occurs by a semiconservative mechanism where each of the plasmid molecules replicates once each cell cycle. 2 micron DNA is the only known example of a multiple-copy, extrachromosomal DNA in which every molecule replicates in each cell cycle. Quantitative analysis of the data indicates that 2 micron DNA replication is limited to a fraction of the cell cycle. The period in the cell cycle when 2 micron DNA replicates was examined directly with synchronous cell cultures. Synchronization was accomplished by sequentially arresting cells in G1 phase using the yeast pheromone alpha-factor and incubating at the restrictive temperature for a cell cycle (cdc 7) mutant. Replication was monitored by adding 3H-uracil to cells previously labeled with 14C-uracil, and determining the 3H/14C ratio for purified DNA species. 2 micron DNA replication did not occur during the G1 arrest periods. However, the population of 2 micron DNA doubled during the synchronous S phase at the permissive temperature, with most of the replication occurring in the first third of S phase. Our results indicate that a mechanism exists which insures that the origin of replication of each 2 micron DNA molecule is activated each S phase. As with chromosomal DNA, further activation is prevented until the next cell cycle. We propose that the mechanism which controls the replication initiation of each 2 micron DNA molecule is identical to that which controls the initiation of chromosomal DNA.
Cell Cycle↗
[Actinomyces rimosus resistance to oxytetracycline].
High frequency of spontaneous and UV-and acridine dye-induced variants susceptible to oxytetracycline (OTC) and deprived of the capacity for synthesizing this antibiotic was observed in strain LST-118 of Actinomyces rimosus. The cells of strain LST-118 of Act. rimosus contained extrachromosomal DNA not found in its OTC susceptible variant BS87, which provides evidence in favour of participation of the extrachromosomal genetic elements in control of OTC resistance of the cells of Act. rimosus, LST-118. The OTC resistance in strain LST-118 is of inducable character. The resistance level is increasing from the beginning of the antibiotic synthesis and initially the subinhibitory concentrations of OTC in the medium were the inductors triggering cellular mechanisms ensuring resistance of the cell to the increasing concentrations of OTC in the medium. The capacity for absorption of OTC in Act rimosus is 2--3 times lower than that in E. coli. The experiments with labeled tetracycline showed that the cells of the actinomycete absorbed OTC when it was present in the medium. The absorption of the main amount of the antibiotic was registered during the first 5 minutes. The difference in absorption of OTC by the cells of the antibiotic resistant and sensitive strains was insignificant.
Acridines↗
Loss of plasmid-mediated resistance after conversion of a group B streptococcus strain to a stable cell wall deficient variant.
A group B streptococcus strain carrying plasmid DNA determining resistance to several drugs was converted by penicillin to cell wall (CW) defective and then to CW deficient variants (L-forms). The stable CW deficient variants became susceptible to antibiotics in study. Dye-buoyant density analysis of the DNA of CW deficient variants showed that the loss of antibiotic resistance was associated with the loss of extrachromosomal DNA.
Anti-Bacterial Agents↗