Structure of an inverted duplication formed as a first step in a gene amplification event: implications for a model of gene amplification.

Passananti, Claudio; Davies, Brendan; Ford, Miriam D.; Fried, Mike

doi:10.1002/j.1460-2075.1987.tb02420.x

Cited by 106 publications

(92 citation statements)

References 29 publications

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“…Populations of SV40 defective genomes were shown to be supercoiled and relaxed circular DNAs of heterogenous sizes (9,28). In some cases the formation of extrachromosomal circles with inverted repeats was proposed to be one of the initial steps of gene amplification (45,51,66,67). Clearly, random overreplication of a portion of ori plasmid-the unstably amplified state-is not beneficial for the stability of the viral genome.…”

Section: Vol 76 2002 Notes 5839mentioning

confidence: 99%

Induction of the Bovine Papillomavirus Origin “Onion Skin”-Type DNA Replication at High E1 Protein Concentrations In Vivo

Männik

Rünkorg

Jaanson

et al. 2002

J Virol

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We have studied the replication of plasmids composed of bovine papillomavirus type 1 (BPV1) origin of replication and expression cartridges for viral proteins E1 and E2 in hamster and mouse cells. We found that the replication mode changed dramatically at different expression levels of the E1 protein. At high levels of the E1 protein, overreplication of the origin region of the plasmid was observed. Analysis of the replication products by one-dimensional and two-dimensional gel electrophoresis suggested that initially "onion skin"-type replication intermediates were generated, presumably resulting from initiation of the new replication forks before the leading fork completed the synthesis of the DNA on the episomal plasmid. These replication intermediates served as templates for generation of a heterogeneous set of origin region-containing linear fragments by displacement synthesis at the partially replicated plasmid. Additionally, the linear fragments may have been generated by DNA break-up of the onion skin-type intermediates. Analysis of replication products indicated that generated linear fragments recombined and formed concatemers or circular molecules, which presumably were able to replicate in an E1-and E2-dependent fashion. At moderate and low levels of E1, generated by transcription of the E1 open reading frame using weaker promoters, DNA replication was initiated at much lower levels, which allowed elongation of the replication fork starting from the origin to be more balanced and resulted in the generation of full-sized replication products.

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Section: Vol 76 2002 Notes 5839mentioning

confidence: 99%

Induction of the Bovine Papillomavirus Origin “Onion Skin”-Type DNA Replication at High E1 Protein Concentrations In Vivo

Männik

Rünkorg

Jaanson

et al. 2002

J Virol

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“…6C), coupled with appropriate end ligation reactions, will produce circular amplicons and a broken chromosome terminated by sequences homologous to some of those in the amplicon. Circles produced by four breaks/ligations will contain imperfect inverted repeats of the type typically found in mammalian amplicons (Ford and Fried 1986;Saito and Stark 1986;Looney and Hamlin 1987;Passananti et al 1987;Hyrien et al 1988;Ruiz and Wahl 1988). The sizes of such extrachromosomal amplicons could easily conform to the majority of amplicon sizes detected at the CHO DHFR locus (Looney et al 1988).…”

Section: A Model For Gene Amplification Involving Chromosome Breakagementioning

confidence: 99%

A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration.

Windle¹,

Draper²,

Yin³

et al. 1991

Genes Dev.

239

147

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A CHO cell line with a single copy of the DHFR locus on chromosome Z2 was used to analyze the structure of the amplification target and products subsequent to the initial amplification event. Dramatic diversity in the number and cytogenetic characteristics of DHFR amplicons was observed as soon as eight to nine cell doublings following the initial event. Two amplicon classes were noted at this early time: Small extrachromosomal elements and closely spaced chromosomal amplicons were detected in 30-40% of metaphases in six of nine clones, whereas three of nine clones contained huge amplicons spanning >50 megabases. In contrast, the incidence of metaphases containing extrachromosomal amplicons fell to 1-2% in cells analyzed at 30-35 cell doublings, and most amplicons localized to rearranged or broken derivatives of chromosome Z2 at this time. Breakage of the Z2 chromosome near the DHFR gene, and deletion of the DHFR gene and flanking DNA was also observed in cells that had undergone the amplification process. To account for these diverse cytogenetic and molecular consequences of gene amplification, we propose that chromosome breakage plays a central role in the amplification process by (1) generating intermediates that are initially acentric and lead to copy number increase primarily by unequal segregation, (2) creating atelomeric ends that are either incompletely replicated or resected by exonucleases to generate deletions, and (3) producing recombinogenic ends that provide preferred sites for amplicon relocalization.

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“…In many cases characterized, these amplified regions contain large ''head-to-head'' duplications (palindromes) of sequences that can be tens to hundreds of kb in size (3)(4)(5)(6)(7)(8). Cytogenetic studies have further revealed that large inverted duplications of a chromosomal region are formed at early stages of gene amplification (9)(10)(11).…”

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confidence: 99%

Short inverted repeats initiate gene amplification through the formation of a large DNA palindrome in mammalian cells

Tanaka

Tapscott

Trask

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

105

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Gene amplification is a common form of genomic instability in a wide variety of organisms and is often associated with tumor progression in mammals. One striking feature of many amplified genes is their organization as large inverted duplications (palindromes). Here, we describe a molecular mechanism for palindrome formation in mammalian cells that is also conserved in protists. We introduced a short (79 or 229 bp) inverted repeat into the genome of Chinese hamster ovary cells and showed that it promoted the formation of a large DNA palindrome after an adjacent DNA double-strand break. This finding suggests that short inverted repeats in the mammalian genome can have a critical role in the initiation of gene amplification. This specific mechanism may provide a novel target for cancer therapies.

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Structure of an inverted duplication formed as a first step in a gene amplification event: implications for a model of gene amplification.

Cited by 106 publications

References 29 publications

Induction of the Bovine Papillomavirus Origin “Onion Skin”-Type DNA Replication at High E1 Protein Concentrations In Vivo

Induction of the Bovine Papillomavirus Origin “Onion Skin”-Type DNA Replication at High E1 Protein Concentrations In Vivo

A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration.

Short inverted repeats initiate gene amplification through the formation of a large DNA palindrome in mammalian cells

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