DNA demethylation and pericentromeric rearrangements of chromosome 1

Ji, Weizhen; Hernandez, R.; Zhang, Xian-Yang; Qu, Guangzhi; Frady, A.; Varela, Maria; Ehrlich, Melanie

doi:10.1016/s0027-5107(97)00088-2

Cited by 173 publications

(119 citation statements)

References 44 publications

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“…10,11,[15][16][17] Studies of ICF lymphoid cells and normal cells treated with DNA methylation inhibitors suggest that DNA hypomethylation can favor pericentromeric rearrangements, including the formation of unstable multiradial chromosomes that may give rise to stable, unbalanced cancer-like DNA rearrangements. 15,16,18,19 This is consistent with a comparative genomic hybridization study showing a significant association between 1qh gain and Chr1 Sat2 hypomethylation in hepatocellular carcinomas. 20 Because pericentromeric rearrangements of Chr1 and Chr16 are overrepresented in diverse cancers and often lead to 1qh gain and 16qh loss, 21 they could participate in tumorigenesis or tumor progression.…”

Section: Introductionsupporting

confidence: 89%

DNA hypomethylation is prevalent even in low-grade breast cancers

Jackson¹,

Yu²,

Arakawa³

et al. 2004

Cancer Biology & Therapy

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109

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Section: Introductionsupporting

confidence: 89%

DNA hypomethylation is prevalent even in low-grade breast cancers

Jackson¹,

Yu²,

Arakawa³

et al. 2004

Cancer Biology & Therapy

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109

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“…In detailed studies of G-banded chromosomes of ICF LCLs from five unrelated patients with DNMT3B mutations, we found that decondensation of the Chr1 juxtacentromeric Sat2-rich region was the most frequent anomaly, and that this decondensation was often seen at the break-points of whole-arm deletions or multiradial chromosomes (three or more Chr1 and/or Chr16 arms fused in the pericentromeric region) (Ehrlich et al, 2001;Tuck-Muller et al, 2000). These results and our findings that 5-azadeoxycytidine or 5-azacytidine treatment of normal lymphoid cultures induces chromosome rearrangements identical to those of ICF lymphoid cells Ji et al, 1997) suggest that DNA hypomethylation predisposes to heterochromatin decondensation, which in turn, facilitates recombination between repeated DNA sequences.…”

Section: Hypomethylation Of Single-copy Genes In Cancersupporting

confidence: 75%

DNA methylation in cancer: too much, but also too little

2002

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Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.

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“…Similar supportive data for this role comes from three papers in 1999 describing mutations in the catalytic domain of the human DNMT3B gene in patients with ICF syndrome (immunode®ciency, centromeric instability, facial anomalies) (Hansen et al, 1999;Okano et al, 1999;Xu et al, 1999). As will be discussed further in the next section, individuals with this disease exhibit profound losses of DNA methylation from satellite 2 and 3 sequences adjacent to the centromeres of chromosomes 1, 9 and 16 resulting in massive instability of these chromosomes (Ji et al, 1997). A speci®c function for Dnmt3a was not detectable with the knockout model but studies using the various Dnmt-knockout ES cells in addition to transgenic Drosophila melanogaster expressing Dnmt3a revealed that this enzyme may be specialized to methylate nonCpG sequences like CpA, and CpT although the function of non-CpG methylation in ES cells is unknown .…”

Section: The Dnmt3 Familymentioning

confidence: 58%

“…For example, V(D)J recombination is reduced more than 100-fold when the recombination substrate is methylated (Hsieh and Lieber, 1992). In addition, Dnmt1 knockout ES cells exhibit a 10-fold increased mutation rate involving gene rearrangements (Chen et al, 1998), and individuals with ICF syndrome or cultured cells treated with 5-azaCdR show increased numbers of chromosomal translocations (Ji et al, 1997;Miniou et al, 1994).…”

Section: Dna Hypomethylation ± Roles In Cancer and Genome Stabilitymentioning

confidence: 99%

DNA methylation, methyltransferases, and cancer

2001

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The ®eld of epigenetics has recently moved to the forefront of studies relating to diverse processes such as transcriptional regulation, chromatin structure, genome integrity, and tumorigenesis. Recent work has revealed how DNA methylation and chromatin structure are linked at the molecular level and how methylation anomalies play a direct causal role in tumorigenesis and genetic disease. Much new information has also come to light regarding the cellular methylation machinery, known as the DNA methyltransferases, in terms of their roles in mammalian development and the types of proteins they are known to interact with. This information has forced a new view for the role of DNA methyltransferases. Rather than enzymes that act in isolation to copy methylation patterns after replication, the types of interactions discovered thus far indicate that DNA methyltransferases may be components of larger complexes actively involved in transcriptional control and chromatin structure modulation. These new ®ndings will likely enhance our understanding of the myriad roles of DNA methylation in disease as well as point the way to novel therapies to prevent or repair these defects. Oncogene (2001) 20, 3139 ± 3155.

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DNA demethylation and pericentromeric rearrangements of chromosome 1

Cited by 173 publications

References 44 publications

DNA hypomethylation is prevalent even in low-grade breast cancers

DNA hypomethylation is prevalent even in low-grade breast cancers

DNA methylation in cancer: too much, but also too little

DNA methylation, methyltransferases, and cancer

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