Sister chromatid fusion initiates amplification of the dihydrofolate reductase gene in Chinese hamster cells.

Ma, Chi; Martin, Stuart; Trask, Barbara J.; Hamlin, Joyce L.

doi:10.1101/gad.7.4.605

Cited by 185 publications

(115 citation statements)

References 50 publications

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“…We, therefore, asked whether PyLT might still lead to genome destabilization and gene ampli®cation and found that this is indeed the case as long as the amino acid sequence decisive for the interaction of PyLT with pRB and the other pocket proteins is intact. Cells selected for the presence of an ampli®ed CAD gene by addition of PALA have higher chromosome number and in addition show the same structures of ampli®ed genes as previously observed in several other cases Windle et al, 1991;Ma et al, 1993;Toledo et al, 1993). The PALA resistant cells appear normal with respect to p53.…”

Section: Discussionsupporting

confidence: 70%

“…However, upon closer inspection of the karyotype of PALA resistant clones ( Figure 2) it became clear that there was not only a higher number of chromosomes but there were chromosomal aberrations visible, in particular dicentric chromosomes, which are thought to be responsible for the generation of ampli®ed genes through bridge breakage fusion (BBF) cycles (reviewed by Stark, 1993). We have, therefore, carried out¯uorescence in situ hybridization (FISH) experiments to analyse ampli®ed CAD gene structures in more detail and indeed found many examples of structures ( Figure 3) as they were repeatedly shown to be characteristic for ampli®ed genes originating through interference with the p53-mediated checkpoint control Windle et al, 1991;Ma et al, 1993;Toledo et al, 1993).…”

Section: Characterization Of Pala Resistant Ref52 Cellsmentioning

confidence: 98%

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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: 70%

Section: Characterization Of Pala Resistant Ref52 Cellsmentioning

confidence: 98%

Polyomavirus large T antigen-dependent DNA amplification

et al. 1997

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“…Dicentric formation has long been considered a mechanism for another endpoint of genetic instability, gene amplification (24,38,42,45). Dicentrics that are formed during gene amplification can initiate another wave of chromosomal instability (25,38). The second possible mechanism for delayed chromosomal instability is related to the delayed induction of micronuclei.…”

Section: Methodsmentioning

confidence: 99%

Delayed chromosomal instability induced by DNA damage.

Marder¹,

Morgan²

1993

Mol. Cell. Biol.

221

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DNA damage induced by ionizing radiation can result in gene mutation, gene amplification, chromosome rearrangements, cellular transformation, and cell death. Although many of these changes may be induced directly by the radiation, there is accumulating evidence for delayed genomic instability following X-ray exposure. We have investigated this phenomenon by studying delayed chromosomal instability in a hamsterhuman hybrid cell line by means of fluorescence in situ hybridization. We examined populations of metaphase cells several generations after expanding single-cell colonies that had survived 5 or 10 Gy of X rays. Delayed chromosomal instability, manifested as multiple rearrangements of human chromosome 4 in a background of hamster chromosomes, was observed in 29%o of colonies surviving 5 Gy and in 62% of colonies surviving 10 Gy. A correlation of delayed chromosomal instability with delayed reproductive cell death, manifested as reduced plating efficiency in surviving clones, suggests a role for chromosome rearrangements in cytotoxicity. There were small differences in chromosome destabilization and plating efficiencies between cells irradiated with 5 or

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“…1-5) [3][4][5][6][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] . This method is now also used to measure NPBs, a biomarker of dicentric chromosomes resulting from telomere end-fusions or DNA misrepair, and to measure NBUDs, a biomarker of gene amplification [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] . The significance of these developments and the concept of the CBMN assay as a ''cytome'' assay of chromosomal instability are explained in the following sections.…”

Section: Introductionmentioning

confidence: 99%

“…This process has been observed in cultures grown under strong selective conditions that induce gene amplification as well as under moderate folic acid deficiency [27][28][29][30][31][32][33][34][35][36][37] . Shimizu et al 31,32 showed, using in vitro experiments with mammalian cells, that amplified DNA is selectively localized to specific sites at the periphery of the nucleus and eliminated via nuclear budding to form MNi during S phase of mitosis.…”

Section: Introductionmentioning

confidence: 99%