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Results for “Extrachromosomal Inheritance”

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PubMed1998

Selective entrapment of extrachromosomally amplified DNA by nuclear budding and micronucleation during S phase.

Acentric, autonomously replicating extrachromosomal structures called double-minute chromosomes (DMs) frequently mediate oncogene amplification in human tumors. We show that DMs can be removed from the nucleus by a novel micronucleation mechanism that is initiated by budding of the nuclear membrane during S phase. DMs containing c-myc oncogenes in a colon cancer cell line localized to and replicated at the nuclear periphery. Replication inhibitors increased micronucleation; cell synchronization and bromodeoxyuridine-pulse labeling demonstrated de novo formation of buds and micronuclei during S phase. The frequencies of S-phase nuclear budding and micronucleation were increased dramatically in normal human cells by inactivating p53, suggesting that an S-phase function of p53 minimizes the probability of producing the broken chromosome fragments that induce budding and micronucleation. These data have implications for understanding the behavior of acentric DNA in interphase nuclei and for developing chemotherapeutic strategies based on this new mechanism for DM elimination.

Antimetabolites↗
PubMed1972

Studies on mitochondria. II. Mitochondrial DNA of thoracic muscles of Schistocerca gregaria.

The buoyant densities of the nuclear and mitochondrial DNA from the thoracic muscles of Schistocerca gregaria were found to be 1 702 and 1.689 g/cm(3), respectively, corresponding to guanine plus cytosine (G + C) content of 42.2 and 30% A preliminary treatment of the mitochondrial pellet with DNase (25 degrees C, 20 min) is necessary to eliminate the contaminating nuclear DNA. The mitochondrial DNA renatures readily after heat denaturation and incubation at 65 degrees C. The DNA released from the mitochondrial pellet by osmotic shock consists of circular open and closed molecules with a contour length around 5 micro The instability of insect mitochondria in in vitro preparations is discussed.

Animals↗
PubMed1981

Protein tightly bound near the termini of the Physarum extrachromosomal rDNA palindrome.

The genes coding for ribosomal RNa in plasmodia of Physarum polycephalum are arranged palindromically on extrachromosomal rDNA molecules of 61 kb (kilobasepairs). Incubation of mildly extracted rDNA with the 125I Bolton-Hunter reagent results in incorporation of label not removed by SDS, CsCl, or various organic solvents. Labeled protein is preferentially associated with terminal rDNA restriction fragments, as detected after gel electrophoresis of the DNA. Antibody reaction with dinitrophenylated protein-rDNA complexes allows visualization of protein located from 1 to 2 kb from the termini, in a region containing multiple inverted repeat sequences and single-strand gaps. DNase I treatment of either rDNA or rDNA termini releases primarily two labeled protein bands of 5,000 and 13,000 daltons as well as less prominent bands of higher molecular weight. We discuss mechanisms for involvement of terminal protein in replication of 3' ends and chromosomal integration of the rDNA.

Base Sequence↗
PubMed1986

Mta, the maternally transmitted antigen, is determined jointly by the chromosomal Hmt and the extrachromosomal Mtf genes.

Mus spretus from four stocks, originating in Spain, Portugal, and Morocco, were tested for the maternally transmitted antigen, Mta. All expressed a variant form not found in other species of mice. Analysis of appropriate crosses with inbred mice showed that the spretus form of Mta is determined by a new allele, c, of the Hmt gene. The Hmtc allele has been isolated in coupling with four different H-2 haplotypes. It is possible to raise CTL specific for the spretus form of Mta. The maternally transmitted factor, Mtf alpha s, of spretus mice determines, in conjunction with the Hmta allele of C57BL/6, an Mta that is indistinguishable from the common form found in C57BL/6 and most other inbred mice. Our experiments show that the specificity of the cell surface antigen Mta is governed jointly by the cytoplasmic gene Mtf and the chromosomal gene Hmt. We propose that Hmt encodes a class I histocompatibility antigen that acts as a restricting element for the Mtf gene product, thus meeting the requirements of T killer cell recognition.

Alleles↗
PubMed1997

Diversity and age of the four major mtDNA haplogroups, and their implications for the peopling of the New World.

Despite considerable investigation, two main questions on the origin of Native Americans remain the topic of intense debate-namely, the number and time of the migration(s) into the Americas. Using the 720 available Amerindian mtDNA control-region sequences, we reanalyzed the nucleotide diversity found within each of the four major mtDNA haplogroups (A-D) thought to have been present in the colonization of the New World. We first verified whether the within-haplogroup sequence diversity could be used as a measure of the haplogroup's age. The pattern of shared polymorphism, the mismatch distribution, the phylogenetic trees, the value of Tajima's D, and the computer simulations all suggested that the four haplogroups underwent a bottleneck followed by a large population expansion. The four haplogroup diversities were very similar to each other, offering a strong support for their single origin. They suggested that the beginning of the Native Americans' ancestral-population differentiation occurred approximately 30,000-40,000 years before the present (ybp), with a 95%-confidence-interval lower bound of approximately 25,000 ybp. These values are in good agreement with the New World-settlement model that we have presented elsewhere, extending the results initially found for haplogroup A to the three other major groups of mtDNA sequences found in the Americas. These results put the peopling of the Americas clearly in an early, pre-Clovis time frame.

Americas↗
PubMed1997

Variable levels of a heteroplasmic point mutation in individual hair roots.

During direct sequencing of the first hypervariable segment of the human mitochondrial control region, we identified one individual with a heteroplasmic point mutation at nt 16,256. We used primer extension to analyze the proportions of each mitochondrial haplotype in peripheral blood, buccal cells, and single hair roots from this individual and from eight members of his maternal lineage. Significant levels of heteroplasmy were found in only three individuals, and, in these cases, the proportions of each haplotype were similar in both blood and buccal cells. From the changes in mitochondrial haplotypes within mother-offspring pairs, we calculated that the most likely size of a mitochondrial bottleneck during development was 1-27 segregating units. However, highly variable levels of heteroplasmy were found in single hair roots, even among roots from the same individual. We analyzed a large number of hair roots from one individual and found that the proportion of one haplotype was within a range of 9% to > 99% in different roots. Roots originating from within a small patch of skin had haplotype proportions as variable as those from different areas of skin.

DNA, Mitochondrial↗
PubMed1980

Evolutionary consequences of intracellular organelle competition.

The review discusses some consequences of the widespread partial uncoupling of the reproduction of organelle DNA from that of nuclear DNA. I propose that in certain circumstances natural selection favors intraorganismal reproductive competition between different varieties of organelle DNA, and in other circumstances selection favors competition between organelle and nuclear DNA. Evidence is marshalled to show that such competition occurs in nature. Situations which would lead to selection for both kinds of competition are described and are shown to be relatively common. A number of examples of apparent competition of predicted kinds are presented. Several testable predictions are made from the theory, and it is shown that the available data are in accord with them. Similar kinds of reproductive competition are predicted to occur in some other symbiotic relationships, and possible examples are presented for two of them: bacterial plasmids and endozoic algae.

Animals↗
PubMed1990

Extrachromosomal HIV-1 DNA in persistently infected U937 cells.

Persistent human immunodeficiency virus type 1 (HIV-1) infection of U937 monocytic cells resulted in the accumulation of novel forms of extrachromosomal viral DNA. These DNA species are larger than the genome size of HIV-1 and persist indefinitely. The extrachromosomal viral DNA species (E-DNA) were shown to be structurally stable by subcloning of infected cell lines and restriction fragment analysis. Similar E-DNA structures were observed in independent infections. Persistently infected monocytic cells had low levels of viral antigens, reflecting the low levels of viral RNA that were detected. These results support a role for E-DNA in persistent HIV-1 infection of monocytic cells.

Cell Line↗
PubMed1983

Extent of BrdUrd-induced prolactin gene amplification in GH cells.

The thymidine analog, 5-bromodeoxyuridine (BrdUrd), induces prolactin (Prl) synthesis and Prl gene amplification in a subclone of GH cells (rat pituitary tumor cells in culture). Withdrawal of drug treatment reverses both processes. Our previous results show that Prl gene amplification is associated with an event involving extrachromosomal DNA. The results presented in this report show that a 20-kb length of DNA, including all the coding sequences of the Prl gene, is amplified following BrdUrd treatment of this strain of GH cells. Amplification of DNA sequences extends about 3 kb upstream from the 5' end and about 7 kb downstream from the 3' end of the Prl gene. The DNA sequences immediately adjacent to these 5'-and 3'-flanking regions of the Prl gene are not affected by BrdUrd treatment. These results suggest that BrdUrd-induced amplification of Prl gene coding and neighboring sequences is restricted to within 3 kb of the 5' end and within 7 kb of the 3' end of the structural gene Analysis of low-molecular-weight extrachromosomal DNA isolated by Hirt's procedure from drug-treated cells reveals a similar pattern of amplification of the Prl gene and its flanking sequences.

Animals↗
PubMed1998

A system for shuttling 200-kb BAC/PAC clones into human cells: stable extrachromosomal persistence and long-term ectopic gene activation.

A novel shuttle vector, pBH140, has been constructed that allows stable maintenance of large genomic inserts as human artificial episomal chromosomes (HAECs) in mammalian cells. The vector, essentially a hybrid BAC-HAEC, contains an F-based replication system as in a bacterial artificial chromosome (BAC) and the Epstein-Barr virus (EBV) latent origin of replication system, oriP, for replication in human cells. A 185-kb DNA insert containing the entire human beta-globin locus, including its locus control region (LCR), was retrofitted into this vector. The resulting beta-globin BAC-HAEC clone, p148BH, was transfected into human cells and analyzed for episomal maintenance and expression of the beta-globin gene. FISH revealed an association of the vector with different human chromosomes but no integration. The beta-globin BAC-HAECs were present at an average copy number of 11-15 per nucleus in the stably transformed human cells. After 1 year of continuous in vitro cultivation, the HAECs persisted as structurally intact 200-kb episomes. While no beta-globin transcription could be detected in the parental D98/Raji cells, correctly spliced RT-PCR products were produced at significant levels in long-term cultures of the BAC-HAEC-transduced cells. The wide availability of BAC and PAC libraries, the ease in manipulating cloned DNA in bacteria, and the episomal stability of the pBH140 vector make this system ideal for studies on gene expression and other genomic functions in human cells. The potential significance of large, functionally active episomes for gene therapy is discussed.

Cell Line, Transformed↗