Inefficient growth arrest in response to dNTP starvation stimulates gene amplification through bridge-breakage-fusion cycles.

Poupon, Marie‐France; Smith, Kathleen A.; Chernova, Olga B.; Gilbert, C; Stark, George R.

doi:10.1091/mbc.7.3.345

Cited by 33 publications

(30 citation statements)

References 28 publications

(41 reference statements)

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“…Only if wild type PyLT is produced at the same time can a fraction of these cells escape the replication block and move into S phase. This scenario thus would be analogous to the one very recently described by Stark and coworkers (Poupon et al, 1996). These authors found that concentrations of PALA which did not lead to a complete G 1 arrest stimulated gene ampli®cation.…”

Section: Discussionsupporting

confidence: 76%

Polyomavirus large T antigen-dependent DNA amplification

et al. 1997

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DNA ampli®cation is a readily measurable indicator for genome destabilization. Contrary to normal senescing cells, those of most immortal or transformed cell lines are karyotypically unstable and permissive for ampli®ca-tion. Permissivity for ampli®cation can be generated by gene products of several DNA tumor viruses whereby their interaction with the tumorsuppressor protein p53 is important. p53 is the major protein involved in check point control of DNA damage. Polyomavirus large T antigen is also involved in immortalization and transformation of cells but it does not interact with p53. We, therefore, examined whether this protein could still make the non-permissive cell line REF52 permissive for gene ampli®cation. To this end REF52 cell lines were constructed which conditionally expressed the wild type polyomavirus large T antigen or a mutant form unable to bind the retinoblastoma protein. Using the inhibitor of de novo pyrimidine biosynthesis, phosphonoacetyl-L-aspartate (PALA), as selective agent we found that PALA resistant cells arise with a frequency of about 5610 75 and that the interaction of polyomavirus large T protein with the retinoblastoma protein or another related pocket protein is important for this to occur. PALA resistant cells have an increased number of chromosomes and dicentric chromosomes which are considered as starting point for DNA structures characteristic for ampli®ed DNA. Such structures were indeed found with the help of uorescence in situ hybridization. PALA resistant cells appear normal with respect to p53. Our data indicate that PALA induces a G 1 block which can be partially overcome by polyomavirus large T protein by its interaction with E2F-pocket protein complexes providing further evidence that these complexes are downstream targets of p53.

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Section: Discussionsupporting

confidence: 76%

Polyomavirus large T antigen-dependent DNA amplification

et al. 1997

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“…In agreement with this model are data demonstrating that a double strand break is su cient to initiate gene ampli®cation (Pipiras et al, 1998). Thus, initiating events in drug-induced gene ampli®cation involve chromosome breakage, deletion, inverted duplication, and terminal fusions (Wahl et al, 1979;Ruiz and Wahl, 1988;Hamlin and Ma, 1990;Smith et al, 1990Smith et al, , 1992Ma et al, 1993;Poupon et al, 1996;Pipiras et al, 1998;Singer et al, 2000).…”

Section: Introductionmentioning

confidence: 75%

“…rDNA ampli®cation in this organism involves speci®c breaks next to inverted repeats (Butler et al, 1996). In mammalian cells, the segregation-driven model includes breakage-bridge-fusion cycles that are instrumental in the generation of drug-induced amplicons Poupon et al, 1996). In agreement with this model are data demonstrating that a double strand break is su cient to initiate gene ampli®cation (Pipiras et al, 1998).…”

Section: Introductionmentioning

confidence: 79%

c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene

Kuschak

Taylor

et al. 2002

Oncogene

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The mechanisms through which the oncoprotein c-Myc initiates locus-speci®c gene ampli®cation are not understood. When analysing the initiation mechanism of cMyc-dependent ampli®cation of the mouse ribonucleotide reductase R2 (R2) gene, we observe c-Myc-dependent initiation of illegitimate DNA replication of the R2 gene. We demonstrate multiple simultaneous c-Myc-induced R2 replication forks, whereas R2 normally replicates with a single fork. In contrast, cyclin C replicates with only a single replication fork irrespective of c-Myc deregulation. In addition to de novo replication forks, cMyc also initiates bi-allelic replication of R2, abrogating its normal mono-allelic replication pattern. Moreover, several chromosomal regions also display c-Myc-induced illegitimate replication pro®les. Thus, c-Myc can act as an illegitimate replication-licensing factor that promotes de novo replication initiation and illegitimate replication timing that adversely impacts upon genomic stability. Oncogene (2002) 21, 909 ± 920.

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“…As noted above, the PALA-resistant cells present in steady state are similar to those that arise during a short period of growth in the rate experiment. Also, some of the events leading to PALA resistance are induced by PALA in both rate and frequency experiments (31,32). The ladder-like structure in two PALA-resistant HT-1080 clones was analyzed in more detail using a centromere-proximal probe, CAD, and a telomere-proximal probe (Fig.…”

Section: Selection Of Human Cell Lines and Fishmentioning

confidence: 99%

Multiple mechanisms of N -phosphonacetyl- l -aspartate resistance in human cell lines: Carbamyl- P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged

Smith

Chernova

Groves

et al. 1997

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

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Inefficient growth arrest in response to dNTP starvation stimulates gene amplification through bridge-breakage-fusion cycles.

Abstract: Cells often acquire resistance to the antiproliferative agents methotrexate (MTX)

Cited by 33 publications

References 28 publications

Polyomavirus large T antigen-dependent DNA amplification

Polyomavirus large T antigen-dependent DNA amplification

c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene

Multiple mechanisms of N -phosphonacetyl- l -aspartate resistance in human cell lines: Carbamyl- P synthetase/aspartate transcarbamylase/dihydro-orotase gene amplification is frequent only when chromosome 2 is rearranged

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