Evidence for a large double-cruciform DNA structure on the X chromosome of human and chimpanzee

Losch, Florian; Bredenbeck, Anne; Hollstein, Verena M.; Walden, Peter; Wrede, Paul

doi:10.1007/s00439-007-0405-4

Cited by 11 publications

(11 citation statements)

References 28 publications

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“…Transfected methylated MAGE-A1 transgenes do not undergo promoter demethylation, and unmethylated MAGE-A1 transgenes become methylated except for the 5′ region in cancer cells (34). Complex chromatin architecture including formation of double cruciform DNA(35) that potentially affects access of methyl binding proteins, DNMTs, and transcription factors such as CTCF, BORIS and SP1(8, 32, 36) may contribute to coordinated repression/activation of CT-X genes within large inverted repeats (7). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer

et al. 2011

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Cancer-testis antigens such as NY-ESO-1, MAGE-A1 and MAGE-A3 are immunogenic proteins encoded by genes, which are normally expressed only in male germ cells, but activated by ill-defined epigenetic mechanisms in human tumors including lung cancers. Previously we reported induction of these cancer-testis antigens in cancer cells, but not normal cells, by DNA demethylating agents and histone deacetylase inhibitors using clinically achievable exposure conditions. In the present study, we evaluated chromatin alterations associated with repression/activation of cancer-testis genes in lung cancer cells to further develop gene induction regimens for cancer immunotherapy. Repression of NY-ESO-1, MAGE-A1, and MAGE-A3 coincided with DNA hypermethylation, recruitment and binding of polycomb group proteins, and histone heterochromatin modifications within the promoters of these genes. De-repression coincided with DNA demethylation, dissociation of polycomb proteins, and presence of euchromatin marks within the respective promoters. ShRNAs were used to inhibit several histone methyl transferases (KMTs) and histone demethylases (KDMs) that mediate histone methylation and repress gene expression. Knockdown of KMT6, KDM1 or KDM5B markedly enhanced deoxyazacytidine (DAC)-mediated activation of these cancer-testis genes in lung cancer cells. DZNep, a pharmacologic inhibitor of KMT6 expression, recapitulated the effects of KMT6 knock-down. Following DAC-DZNep exposure, lung cancer cells were specifically recognized and lysed by allogeneic lymphocytes expressing recombinant T cell receptors recognizing NY-ESO-1 and MAGE-A3. Combining DNA demethylating agents with compounds such as DZNep that modulate histone lysine methylation may provide a novel epigenetic strategy to augment cancer-testis gene expression as an adjunct to adoptive cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer

et al. 2011

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“…Therefore, whereas inverted repeats may suppress random nucleotide changes arising from within their repeating arms [107], they nevertheless represent a structural unit capable of changing genomic orientation over time. We and others [110] have proposed that large inverted repeats may promote strand exchange and form stem-loop structures, which may account for these features [109]. Accordingly (Fig.…”

Section: Genome-wide Analyses and Evolutionary Relationshipsmentioning

confidence: 97%

Non-B DNA structure-induced genetic instability and evolution

Zhao

Bacolla

Wang

et al. 2009

Cell. Mol. Life Sci.

357

350

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Repetitive DNA motifs are abundant in the genomes of various species and have the capacity to adopt non-canonical (i.e. non-B) DNA structures. Several non-B DNA structures, including cruciforms, slipped structures, triplexes, G-quadruplexes, and Z-DNA, have been shown to cause mutations, such as deletions, expansions, and translocations in both prokaryotes and eukaryotes. Their distributions in genomes are not random and often co-localize with sites of chromosomal breakage associated with genetic diseases. Current genome-wide sequence analyses suggest that the genomic instabilities induced by non-B DNA structure-forming sequences not only result in predisposition to disease, but also contribute to rapid evolutionary changes, particularly in genes associated with development and regulatory functions. In this review, we describe the occurrence of non-B DNA-forming sequences in various species, the classes of genes enriched in non-B DNA-forming sequences, and recent mechanistic studies on DNA structure-induced genomic instability to highlight their importance in genomes.

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“…Long IRs (>500 bp), which are rare in the human genome, have been found at sites of gross chromosomal rearrangements (Kurahashi and Emanuel, 2001), and can cause DSBs, stimulating recurrent constitutional translocations in sperm leading to chromosomally unbalanced offspring (Ho et al, 2012; Kurahashi and Emanuel, 2001; Kurahashi et al, 2004; Tanaka et al, 2006). Long IRs can also contribute to deletions, recombination and gene amplifications (Akgun et al, 1997; Cunningham et al, 2003; Gordenin et al, 1993; Losch et al, 2007; Mizuno et al, 2009; Nag and Kurst, 1997; Tanaka et al, 2002; VanHulle et al, 2007; Zhou et al, 2001). In contrast, short perfect IRs are abundant in the human genome, with ~80% being under 100 bp (Wang and Leung, 2006).…”

Section: Introductionmentioning

confidence: 99%

Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

Lu¹,

Wang²,

Bacolla³

et al. 2015

Cell Reports

102

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SUMMARY Analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs) often co-localize with endogenous chromosomal instability and breakage hotspots. Approximately 80% of all IRs in the human genome are short (<100 bp), yet the mutagenic potential of such short cruciform-forming sequences has not been characterized. Here, we found that short IRs are enriched at translocation breakpoints in human cancer, and stimulate the formation of DNA double-strand breaks (DSBs) and deletions in mammalian and yeast cells. We provide evidence for replication-related mechanisms of IR-induced genetic instability and a novel XPF cleavage-based mechanism independent of DNA replication. These new discoveries implicate short IRs as endogenous sources of DNA breakage involved in disease etiology, and suggest that these repeats represent a feature of genome plasticity that may contribute to the evolution of the human genome by providing a means for diversity within the population.

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Evidence for a large double-cruciform DNA structure on the X chromosome of human and chimpanzee

Cited by 11 publications

References 28 publications

Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer

Inhibition of Histone Lysine Methylation Enhances Cancer–Testis Antigen Expression in Lung Cancer Cells: Implications for Adoptive Immunotherapy of Cancer

Non-B DNA structure-induced genetic instability and evolution

Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

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