5-Azacytidine-induced undercondensations in human chromosomes

Schmid, Michael; Haaf, Thomas; Grunert, D.

doi:10.1007/bf00291352

Cited by 117 publications

(64 citation statements)

References 13 publications

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“…The pericentromeric decondensation is a consistent feature that is readily understood in terms of hypomethylation. In fact, the similarity of the cytogenetic features of ICF to 5-azacytidine-induced cytological abnormalities in normal cells (30,31) led investigators to look for hypomethylation in centromeric regions of ICF. Abnormal pairing of the affected centromeric regions also occurs in ICF somatic cells.…”

Section: Discussionmentioning

confidence: 99%

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

Hansen

Wijmenga

Luo

et al. 1999

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

678

416

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DNA methylation is an important regulator of genetic information in species ranging from bacteria to humans. DNA methylation appears to be critical for mammalian development because mice nullizygous for a targeted disruption of the DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA methyltransferase mutations have been reported in humans until now. We describe here the first example of naturally occurring mutations in a mammalian DNA methyltransferase gene. These mutations occur in patients with a rare autosomal recessive disorder, which is termed the ICF syndrome, for immunodeficiency, centromeric instability, and facial anomalies. Centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in their pericentromeric satellite regions. We are able to complement this hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells, suggesting that the ICF gene is conserved in the hamster and promotes de novo methylation. ICF has been localized to a 9-centimorgan region of chromosome 20 by homozygosity mapping. By searching for homologies to known DNA methyltransferases, we identified a genomic sequence in the ICF region that contains the homologue of the mouse Dnmt3b methyltransferase gene. Using the human sequence to screen ICF kindreds, we discovered mutations in four patients from three families. Mutations include two missense substitutions and a 3-aa insertion resulting from the creation of a novel 3 splice acceptor. None of the mutations were found in over 200 normal chromosomes. We conclude that mutations in the DNMT3B are responsible for the ICF syndrome.DNA methylation ͉ somatic cell complementation ͉ consanguinity ͉ RNA splicing

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Section: Discussionmentioning

confidence: 99%

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

Hansen

Wijmenga

Luo

et al. 1999

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

678

416

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“…In this context, we consider epigenetic modifications to be mitotically transmissible alterations that affect the expression of the locus without changing primary DNA sequence (2). One possible epigenetic mechanism (model 2) involves alteration in chromatin structure secondary to changes in cytosine methylation (37)(38)(39). Position-effect variegation in Drosophila provides one example of epigenetic defects based on the propagation of altered chromatin structures (40).…”

Section: Discussionmentioning

confidence: 99%

Developmental abnormalities and epimutations associated with DNA hypomethylation mutations.

Kakutani

Jeddeloh

Flowers

et al. 1996

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

358

273

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A number of aberrant morphological phenotypes were noted during propagation of the Arabidopsis thaliana DNA hypomethylation mutant, ddm1, by repeated self-pollination. Onset of a spectrum of morphological abnormalities, including defects in leaf structure, flowering time, and flower structure, was strictly associated with the ddm1 mutations. The morphological phenotypes arose at a high frequency in selfed ddm1 mutant lines and some phenotypes became progressively more severe in advancing generations. The transmission of two common morphological trait syndromes in genetic crosses demonstrated that the phenotypes are caused by heritable lesions that develop in ddm1 mutant backgrounds. Loss of cytosine methylation in specific genomic sequences during the selfing regime was noted in the ddm1 mutants. Potential mechanisms for formation of the lesions underlying the morphological abnormalities are discussed.

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“…Our results with ethionine, which is considered to be a hypomethylating agent, supports this idea. As observed by others, GC rich regions are particularly sensitive to the decondensation effects of 5-azacytidine (Fucik et al, 1970;Hori, 1983;Parrow et al, 1989;Schmid et al, 1984). The decondensation or out of cycle condensation effects may be responsible for the formation of the chromatid bridges (incomplete untangling of the chromatids) before separation in anaphase.…”

Section: Discussionmentioning

confidence: 81%

“…2). 5-Azacytidine has been reported to interfere with chromosome condensation (Fucik et al, 1970;Hori, 1983;Parrow et al, 1989;Schmid et al, 1984). Berenil, which causes chromosome undercondensation by binding to the minor groove of the DNA molecule, also induced micronuclei (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We have reported that this compound induces micronuclei in SHE cells . Effects such as chromosome decondensation, endoreduplication and segmentation have also been reported (Hori, 1983;Parrow et al, 1989;Schmid et al, 1984). Major perturbations of cell cycle kinetics tagether with elevated rates of endomitosis and tetraploidy were found in human fibroblast-Iike cells from skin and amniotic fluid (Poot et al, 1990).…”

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confidence: 98%

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Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells

Stopper¹,

Körber²,

Schiffmann³

et al. 1993

Mutation Research/Genetic Toxicology

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Summary 5-Azacytidine was originally developed to treat human myelogenous leukemia. However, interest in this compound has expanded because of reports of its ability to affect cell differentiation and to alter eukaryotic gene expression. In an ongoing attempt to understand the biochemical effects of this compound, we examined the effects of 5-azacytidine on mitosis and on micronucleus formation in mammalian cells. In L5178Y mouse cells, 5-azacytidine induced micronuclei at concentrations at which we and others have already reported its mutagenicity at the tk locus. Using CREST staining and C-banding studies, we showed that the induced micronuclei contained mostly chromosomal fragments although some may have contained whole chromosomes. By incorporating BrdU into the DNA of SHE cells, we determined that micronuclei were induced only when the compound was added while the cells were in S phase. Microscopically visible effects due to 5-azacytidine treatment were not observed until anaphase of the mitosis following treatment or thereafter. 5-Azacytidine did not induce micronuclei via interference with formation of the metaphase chromosome arrangement in mitosis, a common mechanism leading to aneuploidy. SupravitalUV microscopy revealed that chromatid bridges were observed in anaphase and, in some cases, were sustained into interphase. In the first mitosis after 5-azacytidine treatment we observed that many cells were unable to perform anaphase separation. All of these observations indicate that 5-azacytidine is predominantly a clastogen through its incorporation into DNA.

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5-Azacytidine-induced undercondensations in human chromosomes

Cited by 117 publications

References 13 publications

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

Developmental abnormalities and epimutations associated with DNA hypomethylation mutations.

Cell-cycle dependent micronucleus formation and mitotic disturbances induced by 5-azacytidine in mammalian cells

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