Clonal inheritance of the pattern of DNA methylation in mouse cells.

Stein, Reuven; Gruenbaum, Yosef; Pollack, Yaakov; Razin, Aharon; Cedar, Howard

doi:10.1073/pnas.79.1.61

Cited by 207 publications

(106 citation statements)

References 30 publications

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“…The methylation status of a transfected gene is largely retained over time in culture (Stein et al, 1982). This was confirmed in our system (examples are the two successive cycles of selection of the wt/mut A tr 1 and 2 in Figure 5).…”

Section: Methylation Status Of the Trop1 Gene Versus Gene Amplificationsupporting

confidence: 62%

Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

et al. 2003

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p53 and DNA methylation play key roles in the maintenance of genome stability. In this work, we demonstrate that the two mechanisms are linked and that p53 plays a role in the maintenance of the DNA methylation levels. The loss of p53 was shown to induce loss of DNA methylation in the TROP1 gene, a human cancer-expressed locus that undergoes amplification when hypomethylated. This demethylation was reverted by the reintroduction of a wild-type TP53 (wtTP53) in the TP53-null cells. Using a gene-amplification assay in vivo, we demonstrate that the loss of p53 leads to a demethylationdependent TROP1 gene amplification. The induction of gene amplification was reverted by the expression of a wtTP53 gene or by in vitro methylation of the transfected DNA with the Sss I DNA methylase. Taken together, these findings demonstrate that the inactivation of TP53 induces loss of DNA methylation and DNA methylationdependent gene amplification.

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Section: Methylation Status Of the Trop1 Gene Versus Gene Amplificationsupporting

confidence: 62%

Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

et al. 2003

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“…The established differentiated methylation pattern is then stably inherited in the somatic cell lines for many generations [14] by a maintenance methylase [15]. The absence of DNA methylation in Drosophila suggests that whatever the clonal inherited pattern of DNA methylation in mammalian DNA reflects, it must be substituted by some other, yet unknown, mechanism in Drosophila.…”

mentioning

confidence: 99%

The absence of detectable methylated bases in Drosophila melanogaster DNA

et al. 1982

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“…2 These patterns are then propagated in subsequent cell divisions by a maintenance methylation reaction in which methylated CpGs rendered hemimethylated by DNA synthesis, are restored to the fully methylated state after a DNA methyltransferase-catalyzed transfer of a methyl group from S-adenosylmethionine to the cytosine in the nascent DNA strand. 3,4 The genome thus encodes both genetic and epigenetic information that is coordinately inherited during DNA replication. The heritability of DNA methylation with somatic cell division allows for the transmission of silent gene states, and plays an integral role in maintaining the stable repression of genes on the inactive X-chromosome, parentally imprinted alleles, and endogenous retroelements in differentiated cells.…”

Section: Introductionmentioning

confidence: 99%

DNMT1 is a Component of a Multiprotein DNA Replication Complex

Vertino¹,

Sekowski²,

Coll³

et al. 2002

Cell Cycle

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DNA methylation is a major determinant of epigenetic inheritance and plays an important role in genome stability. The accurate propagation of DNA methylation patterns with cell division requires that methylation be closely coupled to DNA replication, however the precise molecular determinants of this interaction have not been defined. In the present study, we show that the predominant DNA methyltransferase species in somatic cells, DNMT1, is a component of a multiprotein DNA replication complex termed the DNA synthesome that fully supports semi-conservative DNA replication in a cell-free system. DNMT1 protein and activity were found to co-purify with the human DNA synthesome through a series of subcellular fractionation and chromatography steps, resulting in an enrichment of methyltransferase specific activity from two human cell lines. DNA methyltransferase activity co-eluted with in vitro replication activity and DNA polymerase α activity on sucrose density gradients suggesting that DNMT1 is a tightly bound, core component of the replication complex. The synthesome-associated pool of DNA methyltransferase exhibited both maintenance and de novo methyltransferase activity and the ratio of the two was similar to that observed in whole cell lysates and for recombinant DNMT1. These data indicate that interactions within the synthesome complex do not influence the intrinsic preference of DNMT1 for hemimethylated DNA, but suggest that newly replicated DNA may be subject to low level de novo methylation. The data indicate that DNA methylation is tightly coupled to replication through physical interaction of DNMT1 and core components of the replication machinery. The definition of the molecular interactions between DNMT1 and other proteins in the replication complex in normal and neoplastic cells will provide further insight into the regulation of DNA methylation and the mechanisms underlying the alteration of DNA methylation patterns during carcinogenesis.

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Clonal inheritance of the pattern of DNA methylation in mouse cells.

Cited by 207 publications

References 30 publications

Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

Mutations of TP53 induce loss of DNA methylation and amplification of the TROP1 gene

The absence of detectable methylated bases in Drosophila melanogaster DNA

DNMT1 is a Component of a Multiprotein DNA Replication Complex

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