NAR Top Articles - Surveys and Summaries
Homologous recombination and its regulation
Krejci, L; Altmannova, V; Spirek, M; Zhao, XL
Nucleic Acids Res. (2012) 40 (13): 5795-5818
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Homologous recombination (HR) is critical both for repairing DNA lesions in mitosis and for chromosomal pairing and exchange during meiosis. However, some forms of HR can also lead to undesirable DNA rearrangements. Multiple regulatory mechanisms have evolved to ensure that HR takes place at the right time, place and manner. Several of these impinge on the control of Rad51 nucleofilaments that play a central role in HR. Some factors promote the formation of these structures while others lead to their disassembly or the use of alternative repair pathways. In this article, we review these mechanisms in both mitotic and meiotic environments and in different eukaryotic taxa, with an emphasis on yeast and mammal systems. Since mutations in several proteins that regulate Rad51 nucleofilaments are associated with cancer and cancer-prone syndromes, we discuss how understanding their functions can lead to the development of better tools for cancer diagnosis and therapy.
Comprehensive literature review and statistical considerations for microarray meta-analysis
Tseng, GC; Ghosh, D; Feingold, E
Nucleic Acids Res. (2012) 40 (9): 3785-3799
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With the rapid advances of various high-throughput technologies, generation of '-omics' data is commonplace in almost every biomedical field. Effective data management and analytical approaches are essential to fully decipher the biological knowledge contained in the tremendous amount of experimental data. Meta-analysis, a set of statistical tools for combining multiple studies of a related hypothesis, has become popular in genomic research. Here, we perform a systematic search from PubMed and manual collection to obtain 620 genomic meta-analysis papers, of which 333 microarray meta-analysis papers are summarized as the basis of this paper and the other 249 GWAS meta-analysis papers are discussed in the next companion paper. The review in the present paper focuses on various biological purposes of microarray meta-analysis, databases and software and related statistical procedures. Statistical considerations of such an analysis are further scrutinized and illustrated by a case study. Finally, several open questions are listed and discussed.
Experimental strategies for microRNA target identification
Thomson, DW; Bracken, CP; Goodall, GJ
Nucleic Acids Res. (2011) 39 (16): 6845-6853
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MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression in most biological processes. They act by guiding the RNAi-induced silencing complex (RISC) to partially complementary sequences in target mRNAs to suppress gene expression by a combination of translation inhibition and mRNA decay. The commonly accepted mechanism of miRNA targeting in animals involves an interaction between the 5'-end of the miRNA called the 'seed region' and the 3' untranslated region (3'-UTR) of the mRNA. Many target prediction algorithms are based around such a model, though increasing evidence demonstrates that targeting can also be mediated through sites other than the 3'-UTR and that seed region base pairing is not always required. The power and validity of such in silico data can be therefore hindered by the simplified rules used to represent targeting interactions. Experimentation is essential to identify genuine miRNA targets, however many experimental modalities exist and their limitations need to be understood. This review summarizes and critiques the existing experimental techniques for miRNA target identification.
Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes
de Groote, ML; Verschure, PJ; Rots, MG
Nucleic Acids Res. (2012) 40 (21): 10596-10613
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Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific DNA binding domains. The appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. Various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. Features of such studies provide critical aspects for further improving EGE. An example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes...
Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs
Moran, VA; Perera, RJ; Khalil, AM
Nucleic Acids Res. (2012) 40 (14): 6391-6400
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The recent discovery that the human and other mammalian genomes produce thousands of long non-coding RNAs (lncRNAs) raises many fascinating questions. These mRNA-like molecules, which lack significant protein-coding capacity, have been implicated in a wide range of biological functions through diverse and as yet poorly understood molecular mechanisms. Despite some recent insights into how lncRNAs function in such diverse cellular processes as regulation of gene expression and assembly of cellular structures, by and large, the key questions regarding lncRNA mechanisms remain to be answered. In this review, we discuss recent advances in understanding the biology of lncRNAs and propose avenues of investigation that may lead to fundamental new insights into their functions and mechanisms of action. Finally, as numerous lncRNAs are dysregulated in human diseases and disorders, we also discuss potential roles for these molecules in human health.
5''-UTR RNA G-quadruplexes: translation regulation and targeting
Bugaut, A; Balasubramanian, S
Nucleic Acids Res. (2012) 40 (11): 4727-4741
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RNA structures in the untranslated regions (UTRs) of mRNAs influence post-transcriptional regulation of gene expression. Much of the knowledge in this area depends on canonical double-stranded RNA elements. There has been considerable recent advancement of our understanding of guanine(G)-rich nucleic acids sequences that form four-stranded structures, called G-quadruplexes. While much of the research has been focused on DNA G-quadruplexes, there has recently been a rapid emergence of interest in RNA G-quadruplexes, particularly in the 5'-UTRs of mRNAs. Collectively, these studies suggest that RNA G-quadruplexes exist in the 5'-UTRs of many genes, including genes of clinical interest, and that such structural elements can influence translation. This review features the progresses in the study of 5'-UTR RNA G-quadruplex-mediated translational control. It covers computational analysis, cell-free, cell-based and chemical biology studies that have sought to elucidate the roles of RNA G-quadruplexes in both cap-dependent and -independent regulation of mRNA translation. We also discuss protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target...
Comprehensive literature review and statistical considerations for GWAS meta-analysis
Begum, F; Ghosh, D; Tseng, GC; Feingold, E
Nucleic Acids Res. (2012) 40 (9): 3777-3784
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Over the last decade, genome-wide association studies (GWAS) have become the standard tool for gene discovery in human disease research. While debate continues about how to get the most out of these studies and on occasion about how much value these studies really provide, it is clear that many of the strongest results have come from large-scale mega-consortia and/or meta-analyses that combine data from up to dozens of studies and tens of thousands of subjects. While such analyses are becoming more and more common, statistical methods have lagged somewhat behind. There are good meta-analysis methods available, but even when they are carefully and optimally applied there remain some unresolved statistical issues. This article systematically reviews the GWAS meta-analysis literature, highlighting methodology and software options and reviewing methods that have been used in real studies. We illustrate differences among methods using a case study. We also discuss some of the unresolved issues and potential future directions.
Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication
Sorensen, CS; Syljuasen, RG
Nucleic Acids Res. (2012) 40 (2): 477-486
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Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases...
Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies
Bresnick, EH; Katsumura, KR; Lee, HY; Johnson, KD; Perkins, AS
Nucleic Acids Res. (2012) 40 (13): 5819-5831
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Numerous examples exist of how disrupting the actions of physiological regulators of blood cell development yields hematologic malignancies. The master regulator of hematopoietic stem/progenitor cells GATA-2 was cloned almost 20 years ago, and elegant genetic analyses demonstrated its essential function to promote hematopoiesis. While certain GATA-2 target genes are implicated in leukemogenesis, only recently have definitive insights emerged linking GATA-2 to human hematologic pathophysiologies. These pathophysiologies include myelodysplastic syndrome, acute myeloid leukemia and an immunodeficiency syndrome with complex phenotypes including leukemia. As GATA-2 has a pivotal role in the etiology of human cancer, it is instructive to consider mechanisms underlying normal GATA factor function/regulation and how dissecting such mechanisms may reveal unique opportunities for thwarting GATA-2-dependent processes in a therapeutic context. This article highlights GATA factor mechanistic principles, with a heavy emphasis on GATA-1 and GATA-2 functions in the hematopoietic system, and new links between GATA-2 dysregulation and human pathophysiologies.
Transcription factories in the context of the nuclear and genome organization
Razin, SV; Gavrilov, AA; Pichugin, A; Lipinski, M; Iarovaia, OV; Vassetzky, YS
Nucleic Acids Res. (2011) 39 (21): 9085-9092
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In the eukaryotic nucleus, genes are transcribed in transcription factories. In the present review, we re-evaluate the models of transcription factories in the light of recent and older data. Based on this analysis, we propose that transcription factories result from the aggregation of RNA polymerase II-containing pre-initiation complexes assembled next to each other in the nuclear space. Such an aggregation can be triggered by the phosphorylation of the C-terminal domain of RNA polymerase II molecules and their interaction with various transcription factors. Individual transcription factories would thus incorporate tissue-specific, co-regulated as well as housekeeping genes based only on their initial proximity to each other in the nuclear space. Targeting genes to be transcribed to protein-dense factories that contain all factors necessary for transcription initiation and elongation through chromatin templates clearly favors a more economical utilization and better recycling of the transcription machinery.
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