Unstable and stable CAD gene amplification: importance of flanking sequences and nuclear environment in gene amplification.

Meinkoth, Judy L.; Killary, Ann M.; Fournier, R. E. K.; Wahl, Geoffrey M.

doi:10.1128/mcb.7.4.1415

Cited by 24 publications

(10 citation statements)

References 44 publications

(49 reference statements)

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“…Gene ampli®cation has been studied in in vitro models, mostly using DNA synthesis-inhibiting drugs (Wahl et al, 1979;Brown et al, 1983;Johnston et al, 1983;Knudson, 1986;Meinkoth et al, 1987;Schimke, 1988;Tlsty et al, 1989;Smith et al, 1990Smith et al, , 1992. Gene ampli®cation is thought to initiate through either replication-or segregation-driven mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

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

Kuschak

Taylor

et al. 2002

Oncogene

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“…First, the DMs observed in single cells in these and other cell lines are usually variable in size and are sometimes barely detectable by light microscopy (14,15 (10,19). In T5S1-3, the CAD genes are amplified intrachromosomally, while in C5R500 they localize to extrachromosomal supercoiled -250-kbp circular molecules (10 (20), many of which are presented as inverted repeats (6).…”

mentioning

confidence: 99%

Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules.

Hoff

VanDevanter

Yucel

et al. 1988

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

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118

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Amplification of genes can sometimes be detected by molecular hybridization but not by cytogenetic methods, suggesting that in some cases the units of amplification may be too small to be detected by light microscopy. The experiments reported here investigate whether submicroscopic amplification units are present in early passages of the human tumor cell lines HL-60 and COLO 320. The results show that such cells do contain submicroscopic, extrachromosomal, supercoiled circular molecules harboring MYC genes. The molecules in HL-60 are -250 kilobase pairs (kbp), while those in COLO 320 are 120-160 kbp. The extrachromosomal molecules in HL-60 are shown to replicate semiconservatively and approximately once in one cell cycle. We propose that these submicroscopic elements are precursors of double-minute chromosomes, the usual extrachromosomal manifestation of gene amplification, since both are structurally similar and replicate autonomously.The large number of oncogenes and drug-resistance genes subject to amplification indicates that many, possibly most, genomic regions are capable of undergoing regional increases in copy number (see refs. 1-3 for review). Cytogenetic analyses of many independently isolated cell lines containing different amplified genes show that amplified sequences localize to two types of abnormal chromosomal structures, referred to as double-minute chromosomes (DMs) and expanded chromosomal regions (also called homogeneously staining or abnormally banding regions). DMs are acentric extrachromosomal elements, which replicate approximately once per cell cycle and are believed to be circular (4, 5). Expanded chromosomal regions consist of amplification units arranged as both inverted and direct repeats (6-9). Size estimates for individual amplified units of different chromosomal regions range from 250 to >1000 kilobase pairs (kbp)

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“…Redundant initiations at the same chromosomal origin likely would result in the aberrant amplification of surrounding DNA sequences (25,38). Conversion of bilaterally methylated DMIs to their hemimethylated replication products might be used by the replication machinery to mark previously initiated origins and thereby ensure stoichiometric replication of the entire genome.…”

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confidence: 99%

Densely methylated DNA islands in mammalian chromosomal replication origins.

Tasheva¹,

Roufa²

1994

Mol. Cell. Biol.

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Densely methylated DNA sequence islands, designated DMIs, have been observed in two Chinese hamster cell chromosomal replication origins by using a PCR-based chemical method of detection. One of the origins, on5S1, is located within or adjacent to the coding sequence for ribosomal protein S14 on chromosome 2q, and the other, ori-P, is -17 kbp downstream of the dhfr (dihydrofolic acid reductase) locus on chromosome 2p. The DMI in oris14 is 127 bp long, and the DMI in ori-is 516 bp long. Both DMIs are bilaterally methylated (i.e., all dCs are modified to 5-methyl dC) only in cells that are replicating their DNA. When cell growth and DNA replication are arrested, methylation of CpA, CpT, and CpC dinucleotides is lost and the sequence islands display only a subset of their originally methylated CpG dinucleotides. Several possible roles for DMImediated regulation of mammalian chromosomal origins are considered.To investigate the relationship between DNA cytosine methylation and site-specific point mutations in mammalian genes, we analyzed the positions of cytosine methylation in genomic DNA encoding the cloned Chinese hamster ovary (CHO) cell gene for ribosomal protein S14 (RPS14) and compared the methylation sites detected with the position of a recurrent transition mutation affecting the gene's fifth exon (39). During the course of that study, we noted an unusual methylation pattern within a short stretch of the DNA sequence at the 3' end of the gene. Although cytosine methylation at the 5' end and middle of CHO RPS14 occurs exclusively at CpG dinucleotides, in exponentially growing cells actively engaged in DNA replication, we found a unique chromosome segment at the 3' end of the gene in which every dC residue was methylated. Within this densely methylated island (DMI), both DNA strands were fully methylated, and 5-methyl cytosines were detected in CpA, CpT, and CpC as well as CpG dinucleotides.In the accompanying paper, we report that the 3' end of the CHO RPS14 locus also encodes an early-S-phase origin of bidirectional chromosomal DNA replication (OBR) designated oiS14 (40

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Unstable and stable CAD gene amplification: importance of flanking sequences and nuclear environment in gene amplification.

Cited by 24 publications

References 44 publications

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

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

Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules.

Densely methylated DNA islands in mammalian chromosomal replication origins.

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