scholarly journals ALU non-B-DNA conformations, flipons, binary codes and evolution

2020 ◽  
Vol 7 (6) ◽  
pp. 200222 ◽  
Author(s):  
Alan Herbert
Keyword(s):  
Dna Damage ◽  
Epigenetic Modification ◽  
Rapid Change ◽  
Sequence Motifs ◽  
Alu Elements ◽  
Evolutionary Innovation ◽  
Alu Insertion ◽  
Alu Sequence ◽  
Dna Conformations ◽  
Z Dna

ALUs contribute to genetic diversity by altering DNA's linear sequence through retrotransposition, recombination and repair. ALUs also have the potential to form alternative non-B-DNA conformations such as Z-DNA, triplexes and quadruplexes that alter the read-out of information from the genome. I suggest here these structures enable the rapid reprogramming of cellular pathways to offset DNA damage and regulate inflammation. The experimental data supporting this form of genetic encoding is presented. ALU sequence motifs that form non-B-DNA conformations under physiological conditions are called flipons. Flipons are binary switches. They are dissipative structures that trade energy for information. By efficiently targeting cellular machines to active genes, flipons expand the repertoire of RNAs compiled from a gene. Their action greatly increases the informational capacity of linearly encoded genomes. Flipons are programmable by epigenetic modification, synchronizing cellular events by altering both chromatin state and nucleosome phasing. Different classes of flipon exist. Z-flipons are based on Z-DNA and modify the transcripts compiled from a gene. T-flipons are based on triplexes and localize non-coding RNAs that direct the assembly of cellular machines. G-flipons are based on G-quadruplexes and sense DNA damage, then trigger the appropriate protective responses. Flipon conformation is dynamic, changing with context. When frozen in one state, flipons often cause disease. The propagation of flipons throughout the genome by ALU elements represents a novel evolutionary innovation that allows for rapid change. Each ALU insertion creates variability by extracting a different set of information from the neighbourhood in which it lands. By elaborating on already successful adaptations, the newly compiled transcripts work with the old to enhance survival. Systems that optimize flipon settings through learning can adapt faster than with other forms of evolution. They avoid the risk of relying on random and irreversible codon rewrites.

scholarly journals PRDM9 and an Epidemic of Gene Conversion and Non-Homologous Recombination among Alu Elements in Ancestral Gorillas

2017 ◽  
Author(s):  
Aaron C. Wacholder ◽  
David D. Pollock
Keyword(s):  
Gene Conversion ◽  
Repetitive Sequences ◽  
Rapid Change ◽  
Sequence Divergence ◽  
Great Apes ◽  
Sequence Motifs ◽  
Alu Elements ◽  
Strand Breaks ◽  
Genome Wide ◽  
A Genome

AbstractWe performed a genome-wide scan for recombination-mediated interlocus gene conversion and deletion events among a set of orthologous Alu loci in the Great Apes, and were surprised to discover an extreme excess of such events in the gorilla lineage versus other lineages. Gorilla events, but not events in other Great Apes, are strongly associated with a 15 bp motif commonly found in Alu sequences. This result is consistent with evolutionarily transient targeting of the motif by PRDM9, which induces double strand breaks and crossovers during meiosis at specific but rapidly changing sequence motifs. The motif is preferentially found in conversion recipients but not donors, and is substantially depleted in gorillas, consistent with loss of PRDM9 targets by meiotic drive. Recombination probability falls of exponentially with distance between loci, is reduced slightly by sequence divergence, and drops substantially with recipient divergence from the target motif. We identified 16 other high-copy motifs in human, often associated with transposable elements, with lineage-specific depletion and nearby gene conversion signatures, consistent with transient roles as PRDM9 targets. This work strengthens our understanding of recombination-mediated events in evolution and highlights the potential for interactions between PRDM9 and repetitive sequences to cause rapid change in the genome.

scholarly journals Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Takuma Nakatsuka ◽  
Keisuke Tateishi ◽  
Hiroyuki Kato ◽  
Hiroaki Fujiwara ◽  
Keisuke Yamamoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epigenetic Modification ◽  
Histone Methyltransferase ◽  
Preventive Strategy ◽  
Tumor Initiation ◽  
Liver Transcriptome ◽  
Genetic Abnormalities ◽  
Responsive Element ◽  
Induced Apoptosis

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

scholarly journals Colibactin DNA damage signature indicates causative role in colorectal cancer

2019 ◽  
Author(s):  
Paulina J. Dziubańska-Kusibab ◽  
Hilmar Berger ◽  
Federica Battistini ◽  
Britta A. M. Bouwman ◽  
Amina Iftekhar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Human Cancer ◽  
Colorectal Cancers ◽  
Causative Role ◽  
Sequence Motifs ◽  
Dna Double Strand Breaks ◽  
Colon Cells ◽  
Binding Characteristics ◽  
Significant Enrichment ◽  
Dynamics Simulations

AbstractColibactin, a potent genotoxin of Escherichia coli, causes DNA double strand breaks (DSBs) in human cells. We investigated if colibactin creates a particular DNA damage signature in infected cells by identifying DSBs in colon cells after infection with pks+ E.coli. Interestingly, genomic contexts of DSBs were enriched for AT-rich penta-/hexameric sequence motifs, exhibiting a particularly narrow minor groove width and extremely negative electrostatic potential. This corresponded with the binding characteristics of colibactin to double-stranded DNA, as elucidated by docking and molecular dynamics simulations. A survey of somatic mutations at the colibactin target sites of several thousand cancer genomes revealed significant enrichment of the identified motifs in colorectal cancers. Our work provides direct evidence for a role of colibactin in the etiology of human cancer.One sentence summaryWe identify a mutational signature of colibactin, which is significantly enriched in human colorectal cancers.

scholarly journals Primary structure of human ribosomal protein S14 and the gene that encodes it.

1986 ◽  
Vol 6 (8) ◽  
pp. 2774-2783 ◽  
Author(s):  
D D Rhoads ◽  
A Dixit ◽  
D J Roufa
Keyword(s):  
Ribosomal Protein ◽  
Hybrid Cell ◽  
Chinese Hamster ◽  
Housekeeping Genes ◽  
Single Copy ◽  
Sequence Motifs ◽  
Ribosomal Protein Genes ◽  
Alu Sequence ◽  
Exon 1 ◽  
Human Genomic

Chinese hamster ribosomal protein S14 cDNA was used to recognize homologous human cDNA and genomic clones. Human and Chinese hamster S14 protein sequences deduced from the cDNAs are identical. Two overlapping human genomic S14 DNA clones were isolated from a Charon 28 placental DNA library. A fragment of single-copy DNA derived from an intron region of one clone was mapped to the functional RPS14 locus on human chromosome 5q by using a panel of human X Chinese hamster hybrid cell DNAs. The human S14 gene consists of five exons and four introns spanning 5.9 kilobase pairs of DNA. Polyadenylated S14 transcripts purified from HeLa cell cytoplasma display heterogeneous 5' ends that map within noncoding RPS14 exon 1. This precludes assignment of a unique 5' boundary of RPS14 transcripts with respect to the cloned human genomic DNA. Apparently HeLa cells either initiate transcription at multiple sites within RPS14 exon 1, or capped 5' oligonucleotides are removed from most S14 mRNAs posttranscription. In contrast to the few murine ribosomal protein and several other mammalian housekeeping genes whose structures are known, human RPS14 contains a TATA sequence (TATACTT) upstream from exon 1. Three related short sequence motifs, also observed in murine and yeast ribosomal protein genes, occur in this region of the RPS14 gene. RPS14 introns 3 and 4 both contain Alu sequences. Interestingly, the Alu sequence in intron 3 is located slightly downstream from a chromosome 5 deletion breakpoint in one human X hamster hybrid clone analyzed.

The Effect of the B and Z DNA Conformations on the Introduction of Photodynamic Damage

BioScience ◽  
1983 ◽  
Vol 33 (11) ◽  
pp. 715-716
Author(s):  
Ross S. Feldberg ◽  
Caroline Brown ◽  
Josephine A. Carew ◽  
Judith L. Lucas
Keyword(s):  
Dna Conformations ◽  
Z Dna

scholarly journals Quantification of double stranded DNA breaks and telomere length as proxies for corneal damage and replicative stress in 64 human keratoconus corneas

2018 ◽  
Author(s):  
Robert PL Wisse ◽  
Jonas JW Kuiper ◽  
Timothy RDJ Radstake ◽  
Jasper CA Broen
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Telomere Length ◽  
Morphological Changes ◽  
Corneal Transplant ◽  
Dna Breaks ◽  
Alu Elements ◽  
Contact Lens Wear ◽  
Replicative Stress ◽  
Corneal Sample

AbstractPurposeThe pathogenesis of keratoconus (KC) is multifactorial and associated with oxidative stress and subsequent DNA damage. The aim of this study was to investigate differences in DNA damage and replicative stress in patients with KC, and in both healthy and diseased controls.MethodsSixty-four corneal buttons were obtained from 27 patients with KC after corneal transplant surgery, 21 patients with a decompensated graft (DG), and 16 healthy controls (HC). The amount of intact Alu elements per genome copy as measured by qPCR was used to quantify intact DNA. Telomere length was measured as a proxy for replicative stress. In addition, telomerase reverse transcriptase (hTERT) gene expression level was assessed.ResultsMean (±SD) DNA damage was similar between the KC (5.56 ±14.08), DG (3.16 ±8.22), and HC (3.51 ±6.66) groups (P=0.807). No associations were found between DNA damage and patient age (P=0.523), atopic constitution (P=0.240), or contact lens wear (P=0.393). Telomere length differed (P=0.034), most notably in the KC group, and hTERT was not detected in any corneal sample. Three cross-linked (CXL) KC corneas did not contain significant more DNA damage (2.6x, P = 0.750).ConclusionsBased on these findings, differences in actual corneal DNA damage in KC could not be identified, and the longer telomere length in KC did not support replicative stress as a major etiological factor in the pathogenesis of KC. Future longitudinal investigations on KC etiology should assess progressive early cases to better comprehend the cellular and molecular processes preceding the archetypical morphological changes.PrecisOxidative stress is allegedly linked with the development of keratoconus. Whether these stressors actually lead to persisting DNA damage and replicative stress is debated. DNA damage was comparable with control samples, and a shortened telomere length was not identified.

Primary structure of human ribosomal protein S14 and the gene that encodes it

1986 ◽  
Vol 6 (8) ◽  
pp. 2774-2783
Author(s):  
D D Rhoads ◽  
A Dixit ◽  
D J Roufa
Keyword(s):  
Ribosomal Protein ◽  
Hybrid Cell ◽  
Chinese Hamster ◽  
Housekeeping Genes ◽  
Single Copy ◽  
Sequence Motifs ◽  
Ribosomal Protein Genes ◽  
Alu Sequence ◽  
Exon 1 ◽  
Human Genomic

Chinese hamster ribosomal protein S14 cDNA was used to recognize homologous human cDNA and genomic clones. Human and Chinese hamster S14 protein sequences deduced from the cDNAs are identical. Two overlapping human genomic S14 DNA clones were isolated from a Charon 28 placental DNA library. A fragment of single-copy DNA derived from an intron region of one clone was mapped to the functional RPS14 locus on human chromosome 5q by using a panel of human X Chinese hamster hybrid cell DNAs. The human S14 gene consists of five exons and four introns spanning 5.9 kilobase pairs of DNA. Polyadenylated S14 transcripts purified from HeLa cell cytoplasma display heterogeneous 5' ends that map within noncoding RPS14 exon 1. This precludes assignment of a unique 5' boundary of RPS14 transcripts with respect to the cloned human genomic DNA. Apparently HeLa cells either initiate transcription at multiple sites within RPS14 exon 1, or capped 5' oligonucleotides are removed from most S14 mRNAs posttranscription. In contrast to the few murine ribosomal protein and several other mammalian housekeeping genes whose structures are known, human RPS14 contains a TATA sequence (TATACTT) upstream from exon 1. Three related short sequence motifs, also observed in murine and yeast ribosomal protein genes, occur in this region of the RPS14 gene. RPS14 introns 3 and 4 both contain Alu sequences. Interestingly, the Alu sequence in intron 3 is located slightly downstream from a chromosome 5 deletion breakpoint in one human X hamster hybrid clone analyzed.

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