Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification

Tanaka, Hisashi; Bergstrom, Donald A.; Meng, Yao; Tapscott, Stephen J.

doi:10.1038/ng1515

Cited by 99 publications

(131 citation statements)

References 47 publications

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“…Sequence homology profiling analysis supports the concept of the trans-SNP/microRNA master regulatory network operating via microRNA signaling and intron/exon cross-talk between SNP host genes and microRNA target genes. Intriguingly, many chromosomal components of this regulatory network were previously defined as chromosomal regions frequently targeted for palindrome-driven DNA amplification in human cancers 29 as well as common malignancy-associated regions of recurrent transcriptional activation (MARTA) in human breast, prostate, ovarian and colon cancers. 30,31 Evolutionary consequences of the genome-scale pervasive transcription.…”

Section: Resultsmentioning

confidence: 99%

Phenotype-defining functions of multiple non-coding RNA pathways

Glinsky

2008

Cell Cycle

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One of the surprising revelations of the initial stage of the ENCODE project was the conclusion that more than 90% of human genome is transcribed. A major component of this vast transcriptional output is represented by highly heterogeneous families of transcripts defined as short non-coding RNAs (sncRNAs) with no or limited protein-coding potentials. Here we carried out the sequence homolog profiling of the 2301 human sncRNAs with confirmed sequence identities [including 943 transintrons; 235 expressed distal intergenic sequences (EDIS); and 1005 piRNAs] as well as >1000 hypothetical transcripts derived from allelic variants of human SNP sequences with strong associations to human diseases or linkages to phenotypes established in genome-wide association studies. Unexpectedly, this analysis reveals a structural feature common for ~85% of analyzed sncRNA sequences and 488 human microRNAs. This structural feature common for multiple seemingly unrelated sncRNA pathways points to a multitude of potential functional and regulatory implications involving mechanisms of gene expression regulation, control of biogenesis, stability and bioactivity of microRNAs, sncRNA-guided macromolecular interactions, and transcriptional basis of self/non-self discrimination by immune system. Our analysis implies that hundreds thousands of nonprotein-coding transcripts are contributing to phenotype-defining regulatory and structural features of a cell. Therefore, definitions of genes as structural elements of a genome contributing to phenotypes should be expanded beyond the physical boundaries of mRNA-encoding units. We propose an information-centered model of a cell suggesting that informasomes (the RNP complexes of sncRNAs and Argonaute proteins) represent the intracellular structures which provide the increasingly complex structural framework of genomic regulatory functions in higher eukaryotes to facilitate the stochastic (random and probabilistic) rather than deterministic mode of choices in a sequence of regulatory events defining the phenotype.

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Section: Resultsmentioning

confidence: 99%

Phenotype-defining functions of multiple non-coding RNA pathways

Glinsky

2008

Cell Cycle

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“…The genome-wide analysis of palindrome formation (GAPF) procedure was performed as described previously (36) with modifications. After snapback treatment, 6 l of S1 nuclease buffer, 4 l of 3 M NaCl, and 100 U of S1 nuclease (Invitrogen) were added to the DNA and incubated at 37°C for 1 h. S1 nuclease was inactivated by addition of 10 mM EDTA and phenol-chloroform extraction.…”

Section: Constructsmentioning

confidence: 99%

“…2a). The fragment in each MTX-resistant clone was converted to half-size after denaturing and rapid cooling (snap-back) (36), indicating that a DSB alone, without an adjacent DNA IR, is sufficient to generate large palindromes. Heterogeneous sizes of palindromic fragments suggest variable processing of I-SceI-induced DSBs.…”

Section: Significant Increase Of Mtx-resistant Clones In Response Tomentioning

confidence: 99%

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Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer

Tanaka

Cao

Bergstrom

et al. 2007

Molecular and Cellular Biology

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Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease. A critical event initiating gene amplification is a DNA double-strand break (DSB), which is immediately followed by the formation of a large DNA palindrome. Large DNA palindromes are frequent and nonrandomly distributed in the genomes of cancer cells and facilitate a further increase in copy number. Although the importance of the formation of large DNA palindromes as a very early event in gene amplification is widely recognized, it is not known how a DSB is resolved to form a large DNA palindrome and whether any local DNA structure determines the location of large DNA palindromes. We show here that intrastrand annealing following a DNA double-strand break leads to the formation of large DNA palindromes and that DNA inverted repeats in the genome determine the efficiency of this event. Furthermore, in human Colo320DM cancer cells, a DNA inverted repeat in the genome marks the border between amplified and nonamplified DNA. Therefore, an early step of gene amplification is a regulated process that is facilitated by DNA inverted repeats in the genome.

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“…Alternatively, a break nearby might result in nucleolytic resection until a region of fold-back stabilizes the DNA end in a hairpin configuration. (103) …”

Section: Classification Of the Mechanism Of Lymphoid Chromosomal mentioning

confidence: 99%

DNA structures at chromosomal translocation sites

Raghavan

Lieber

2006

BioEssays

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SummaryIt has been unclear why certain defined DNA regions are consistently sites of chromosomal translocations. Some of these are simply sequences of recognition by endogenous recombination enzymes, but most are not. Recent progress indicates that some of the most common fragile sites in human neoplasm assume non-B DNA structures, namely deviations from the Watson-Crick helix. Because of the single strandedness within these non-B structures, they are vulnerable to structure-specific nucleases. Here we summarize these findings and integrate them with other recent data for non-B structures at sites of consistent constitutional chromosomal translocations.

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Widespread and nonrandom distribution of DNA palindromes in cancer cells provides a structural platform for subsequent gene amplification

Cited by 99 publications

References 47 publications

Phenotype-defining functions of multiple non-coding RNA pathways

Phenotype-defining functions of multiple non-coding RNA pathways

Intrastrand Annealing Leads to the Formation of a Large DNA Palindrome and Determines the Boundaries of Genomic Amplification in Human Cancer

DNA structures at chromosomal translocation sites

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