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Protection of the genome and the central exome by peripheral non-coding dna against dna damage in health, ageing and age-related diseases

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BIOLOGICAL REVIEWS 2025年第2期100卷 508-529页

作者： Qiu, Guo-Hua Fu, Mingjun Zheng, Xintian Huang, Cuiqin Longyan Univ Coll Life Sci Longyan 364012 Peoples R China Fujian Prov Univ Engn Res Ctr Prevent & Control Anim Origin Zoonosi Fujian Prov Key Lab Prevent Vet Med & Biotechnol Key Lab Prevent & Control Anim Infect Dis & Biotec Longyan Peoples R China

dna in eukaryotic genomes is under constant assault from both exogenous and endogenous sources, leading to dna damage, which is considered a major molecular driver of ageing. Fortunately, the genome and the central exome are safeguarded against these attacks by abundant peripheral non-coding dna. non-coding dna codes for small non-coding RNAs that inactivate foreign nucleic acids in the cytoplasm and physically blocks these attacks in the nucleus. Damage to non-coding dna produced during such blockage is removed in the form of extrachromosomal circular dna (eccdna) through nucleic pore complexes. Consequently, non-coding dna serves as a line of defence for the exome against dna damage. The total amount of non-coding dna/heterochromatin declines with age, resulting in a decrease in both physical blockage and eccdna exclusion, and thus an increase in the accumulation of dna damage in the nucleus during ageing and in age-related diseases. Here, we summarize recent evidence supporting a protective role of non-coding dna in healthy and pathological states and argue that dna damage is the proximate cause of ageing and age-related genetic diseases. Strategies aimed at strengthening the protective role of non-coding dna/heterochromatin could potentially offer better systematic protection for the dynamic genome and the exome against diverse assaults, reduce the burden of dna damage to the exome, and thus slow ageing, counteract age-related genetic diseases and promote a healthier life for individuals.

关键词： non-coding dna genome defence exome dna damage eccdna nucleic pore complex ageing age-related diseases

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Protection of the genome and central protein-coding sequences by non-coding dna against dna damage from radiation

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MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2015年 764卷 108-117页

作者： Qiu, Guo-Hua Changzhou Univ Inst Biomed Engn & Hlth Sci Changzhou Jiangsu Peoples R China

non-coding dna comprises a very large proportion of the total genomic content in higher organisms, but its function remains largely unclear. non-coding dna sequences constitute the majority of peripheral heterochromatin, which has been hypothesized to be the genome's 'bodyguard' against dna damage from chemicals and radiation for almost four decades. The bodyguard protective function of peripheral heterochromatin in genome defense has been strengthened by the results from numerous recent studies, which are summarized in this review. These data have suggested that cells and/or organisms with a higher level of heterochromatin and more non-coding dna sequences, including longer telomeric dna and rdnas, exhibit a lower frequency of dna damage, higher radioresistance and longer lifespan after IR exposure. In addition, the majority of heterochromatin is peripherally located in the three-dimensional structure of genome organization. Therefore, the peripheral heterochromatin with non-coding dna could play a protective role in genome defense against dna damage from ionizing radiation by both absorbing the radicals from water radiolysis in the cytosol and reducing the energy of IR. However, the bodyguard protection by heterochromatin has been challenged by the observation that dna damage is less frequently detected in peripheral heterochromatin than in euchromatin, which is inconsistent with the expectation and simulation results. Previous studies have also shown that the dna damage in peripheral heterochromatin is rarely repaired and moves more quickly, broadly and outwardly to approach the nuclear pore complex (NPC). Additionally, it has been shown that extrachromosomal circular dnas (eccdnas) are formed in the nucleus, highly detectable in the cytoplasm (particularly under stress conditions) and shuttle between the nucleus and the cytoplasm. Based on these studies, this review speculates that the sites of dna damage in peripheral heterochromatin could occur more frequently

关键词： non-coding dna Peripheral heterochromatin Genome protection dna damage Radiation

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Phylogenetics of asterids based on 3 coding and 3 non-coding chloroplast dna markers and the utility of non-coding dna at higher taxonomic levels

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MOLECULAR PHYLOGENETICS AND EVOLUTION 2002年第2期24卷 274-301页

作者： Bremer, B Bremer, K Heidari, N Erixon, P Olmstead, RG Anderberg, AA Källersjö, M Barkhordarian, E Evolutionary Biol Ctr Dept Systemat Bot SE-75236 Uppsala Sweden Univ Washington Dept Bot Seattle WA 98195 USA Swedish Museum Nat Hist Dept Phanerogam Bot SE-10405 Stockholm Sweden Swedish Museum Nat Hist Lab Mol Systemat SE-10405 Stockholm Sweden Royal Swedish Acad Sci Bergius Fdn SE-10405 Stockholm Sweden

Asterids comprise 1/4-1/3 of all flowering plants and are classified in 10 orders and >100 families. The phylogeny of asterids is here explored with jackknife parsimony analysis of chloroplast dna from 132 genera representing 103 families and all higher groups of asterids. Six different markers were used, three of the markers represent protein coding genes, rbcL, ndhF, and matK, and three other represent non-coding dna;a region including trnL exons and the intron and intergenic spacers between trnT (UGU) to trnF (GAA);another region including trnV exons and intron, trnM and intergenic spacers between trnV (UAC) and atpE, and the rps16 intron. The three non-coding markers proved almost equally useful as the three coding genes in phylogenetic reconstruction at the high level of orders and families in asterids, and in relation to the number of aligned positions the non-coding markers were even more effective. Basal interrelationships among Cornales, Ericales, lamiids (new name replacing euasterids 1), and campanulids (new name replacing euasterids 11) are resolved with strong support. Family interrelationships are fully or almost fully resolved with medium to strong support in Cornales, Garryales, Gentianales, Solanales, Aquifoliales, Apiales, and Dipsacales. Within the three large orders Ericales, Lamiales, and Asterales, family interrelationships remain partly unclear. The analysis has contributed to reclassification of several families, e.g., Tetrameristaceae, Ebenaceae, Styracaceae, Montiniaceae, Orobanchaceae, and Scrophulariaceae (by inclusion of Pellicieraceae, Lissocarpaceae, Halesiaceae, Kaliphoraceae, Cyclocheilaceae, and Myoporaceae + Buddlejaceae, respectively), and to the placement of families that were unplaced in the APG-system, e.g., Sladeniaceae, Pentaphylacaceae, Plocospermataceae, Cardiopteridaceae, and Adoxaceae (in Ericales, Ericales, Lamiales, Aquifoliales, and Dipsacales, respectively), and Paracryphiaceae among campanulids. Several families of e

关键词： asterids phylogeny rbcL ndhF matK trnT-F trnV-atpE rps16 coding dna non-coding dna

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Functional interrogation of non-coding dna through CRISPR genome editing

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METHODS 2017年 121卷 118-129页

作者： Canver, Matthew C. Bauer, Daniel E. Orkin, Stuart H. Harvard Med Sch Boston MA 02115 USA Boston Childrens Hosp Div Hematol Oncol Boston MA 02115 USA Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA Howard Hughes Med Inst Boston MA 02115 USA

Methodologies to interrogate non-coding regions have lagged behind coding regions despite comprising the vast majority of the genome. However, the rapid evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has provided a multitude of novel techniques for laboratory investigation including significant contributions to the toolbox for studying non-coding dna. CRISPR-mediated loss-of-function strategies rely on direct disruption of the underlying sequence or repression of transcription without modifying the targeted dna sequence. CRISPR-mediated gain of -function approaches similarly benefit from methods to alter the targeted sequence through integration of customized sequence into the genome as well as methods to activate transcription. Here we review CRISPR-based loss-and gain-of-function techniques for the interrogation of non-coding dna. (C) 2017 Elsevier Inc. All rights reserved.

关键词： non-coding dna CRISPRS (Genetics) GENOME editing EVOLUTION (Biology) PALINDROMIC dna MUTATION (Biology)

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The protective function of non-coding dna in dna damage accumulation with age and its roles in age-related diseases

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BIOGERONTOLOGY 2019年第6期20卷 741-761页

作者： Qiu, Guo-Hua Zheng, Xintian Fu, Mingjun Huang, Cuiqin Yang, Xiaoyan Longyan Univ Fujian Prov Key Lab Prevent & Control Anim Infect Longyan 364012 Peoples R China Longyan Univ Fujian Prov Univ Key Lab Prevent Vet Med & Biotechnol Longyan 364012 Peoples R China Longyan Univ Coll Life Sci Longyan 364012 Peoples R China

Aging is a progressive decline of physiological function in tissue and organ accompanying both accumulation of dna damage and reduction of non-coding dna. Peripheral non-coding dna/heterochromatin has been proposed to protect the genome and centrally-located protein-coding sequences in soma and male germ cells against radiation and the invasion of exogenous nucleic acids. Therefore, this review summarizes the reduction of non-coding dna/heterochromatin (including telomeric dna and rdna) and dna damage accumulation during normal physiological aging and in various aging-related diseases. Based on analysis of data, it is found that dna damage accumulation is roughly negatively correlated with the reduction of non-coding dna and therefore speculated that dna damage accumulation is likely due to the reduction of non-coding dna protection in genome defense during aging. Therefore, it is proposed here that means to increase the total amount of non-coding dna and/or heterochromatin prior to the onset of these diseases could potentially better protect the genome and protein-coding dna, reduce the incidence of aging-related diseases, and thus lead to better health during aging.

关键词： non-coding dna dna damage accumulation Aging-related diseases Peripheral heterochromatin Genome protection

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An Abundant Class of non-coding dna Can Prevent Stochastic Gene Silencing in the C. elegans Germline

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CELL 2016年第2期166卷 343-357页

作者： Frokjaer-Jensen, Christian Jain, Nimit Hansen, Loren Davis, M. Wayne Li, Yongbin Zhao, Di Rebora, Karine Millet, Jonathan R. M. Liu, Xiao Kim, Stuart K. Dupuy, Denis Jorgensen, Erik M. Fire, Andrew Z. Univ Utah Howard Hughes Med Inst Dept Biol Salt Lake City UT 84112 USA Stanford Univ Dept Pathol Stanford CA 94305 USA Univ Copenhagen Dept Biomed Sci DK-2200 Copenhagen N Denmark Univ Copenhagen Danish Natl Res Fdn Ctr Cardiac Arrhythmia DK-2200 Copenhagen N Denmark Stanford Univ Sch Med Dept Bioengn Stanford CA 94305 USA Stanford Univ Med Ctr Dept Dev Biol Stanford CA 94305 USA Univ Bordeaux IECB Lab ARNA INSERMU869 F-33600 Pessac France Stanford Univ Dept Genet Stanford CA 94305 USA Tsinghua Univ Sch Life Sci Beijing 100084 Peoples R China

Cells benefit from silencing foreign genetic elements but must simultaneously avoid inactivating endogenous genes. Although chromatin modifications and RNAs contribute to maintenance of silenced states, the establishment of silenced regions will inevitably reflect underlying dna sequence and/or structure. Here, we demonstrate that a pervasive non-coding dna feature in Caenorhabditis elegans, characterized by 10-base pair periodic A(n)/T-n-clusters ( PATCs), can license transgenes for germline expression within repressive chromatin domains. Transgenes containing natural or synthetic PATCs are resistant to position effect variegation and stochastic silencing in the germline. Among endogenous genes, intron length and PATC-character undergo dramatic changes as orthologs move from active to repressive chromatin over evolutionary time, indicating a dynamic character to the A(n)/T-n periodicity. We propose that PATCs form the basis of a cellular immune system, identifying certain endogenous genes in heterochromatic contexts as privileged while foreign dna can be suppressed with no requirement for a cellular memory of prior exposure.

关键词： Caenorhabditis elegans -- Genetics non-coding dna Gene silencing Nucleotide sequence Germ cells Transgenes

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Genome defense against exogenous nucleic acids in eukaryotes by non-coding dna occurs through CRISPR-like mechanisms in the cytosol and the bodyguard protection in the nucleus

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MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2016年第0期767卷 31-41页

作者： Qiu, Guo-Hua Changzhou Univ Changzhou Jiangsu Peoples R China

In this review, the protective function of the abundant non-coding dna in the eukaryotic genome is discussed from the perspective of genome defense against exogenous nucleic acids. Peripheral non coding dna has been proposed to act as a bodyguard that protects the genome and the central protein coding sequences from ionizing radiation-induced dna damage. In the proposed mechanism of protection, the radicals generated by water radiolysis in the cytosol and IR energy are absorbed, blocked and/or reduced by peripheral heterochromatin;then, the dna damage sites in the heterochromatin are removed and expelled from the nucleus to the cytoplasm through nuclear pore complexes, most likely through the formation of extrachromosomal circular dna. To strengthen this hypothesis, this review summarizes the experimental evidence supporting the protective function of non-coding dna against exogenous nucleic acids. Based on these data, I hypothesize herein about the presence of an additional line of defense formed by small RNAs in the cytosol in addition to their bodyguard protection mechanism in the nucleus. Therefore, exogenous nucleic acids may be initially inactivated in the cytosol by small RNAs generated from non-coding dna via mechanisms similar to the prokaryotic CRISPR-Cas system. Exogenous nucleic acids may enter the nucleus, where some are absorbed and/or blocked by heterochromatin and others integrate into chromosomes. The integrated fragments and the sites of dna damage are removed by repetitive non-coding dna elements in the heterochromatin and excluded from the nucleus. Therefore, the normal eukaryotic genome and the central protein-coding sequences are triply protected by non-coding dna against invasion by exogenous nucleic acids. This review provides evidence supporting the protective role of non-coding dna in genome defense. (C) 2016 Elsevier B.V. All rights reserved.

关键词： non-coding dna Genome defense CRISPR-like Bodyguard protection Viruses

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Searching for functional genetic variants in non-coding dna

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CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 2008年第4期35卷 372-375页

作者： Cobb, Joanna Busst, Cara Petrou, Steven Harrap, Stephen Ellis, Justine Univ Melbourne Dept Physiol Melbourne Vic 30101 Australia Howard Florey Inst Melbourne Vic Australia Murdoch Childerns Res Inst Melbourne Vic Australia

1. The search for dna sequence variants for complex human polygenic conditions has been a strong focus of recent genetic research. While gene loci have been identified, few variants in the coding sequences of these genes have been found, suggesting that non-coding sequence variation may underlie many complex conditions. 2. non-coding dna harbours regulatory elements capable of making changes to gene expression. However, regulatory dna sequences are currently difficult to recognize and their function is poorly understood, complicating the task of assigning potential functional significance to non-coding variation. 3. Comparative genomics, the study of evolutionary dna conservation, has enabled the emergent field of non-coding dna identification in human disease analysis. 4. This brief review will focus on the potential of a relatively high throughput technique based on comparative genomics, that may aid in the identification of functionally important non-coding sequence variation in complex diseases.

关键词： comparative genomics enhancer screening non-coding dna

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Decoding non-coding dna: Trash or Treasure?

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RESONANCE-JOURNAL OF SCIENCE EDUCATION 2011年第4期16卷 333-340页

作者： Iyer, Namrata Indian Inst Sci Dept Microbiol & Cell Biol Bangalore 560012 Karnataka India

non-coding dna, once thought of as 'junk', represents a very large portion of an organism's genome. However, recent research has brought to light many functional elements present within non-coding dna sequences and unravelled a fascinating array of functions performed by these elements. These findings have highlighted the nature of the evolutionary forces that led to the accumulation and retention of non-coding dna. In this article, the various elements present within non-coding dna, their functional relevance to the cell and the changing perspective of the scientific community towards this so-called 'junk' dna have been described.

关键词： non-coding dna transposons repeat elements pseudogenes

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Hairpins create minute inversions in non-coding regions of chloroplast dna

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CURRENT GENETICS 1996年第3期30卷 259-262页

作者： Kelchner, SA Wendel, JF IOWA STATE UNIV DEPT BOTAMESIA 50011

Minute inversions (4 bp in length), associated with probable hairpin secondary structures, were inferred from comparative analysis of rp116 intron sequences from the chloroplast genomes of Chusquea species and related bamboos (Poaceae). The inverted sequences, which appear to have arisen independently on several occasions, comprise entire loops of the putative hairpins. The process of inversion seems dependent upon the stem length of the hairpin and its estimated free energy of formation. A similar inversion was uncovered for other plants in a previously published data set for a different non-coding region of the chloroplast genome, suggesting that the inversional process may be a common feature of non-coding dna evolution. Several implications for phylogenetic analysis are noted.

关键词： inversions non-coding dna phylogenetics molecular evolution rpl16 intron

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