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Panagiotis Kotsantis, Lara Marques Silva, Sarah Irmscher, Rebecca M Jones, Lisa Folkes, Natalia Gromak, Eva Petermann
Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRAS(V12) promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRAS(V12), elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage...
October 11, 2016: Nature Communications
Zachary T Beck, Zheng Xing, Elizabeth J Tran
The survival of all organisms is dependent on complex, coordinated responses to environmental cues. Non-coding RNAs have been identified as major players in regulation of gene expression, with recent evidence supporting roles for long non-coding (lnc)RNAs in both transcriptional and post-transcriptional control. Evidence from our laboratory shows that lncRNAs have the ability to form hybridized structures called R-loops with specific DNA target sequences in S. cerevisiae, thereby modulating gene expression...
October 4, 2016: RNA Biology
Peter Zeller, Jan Padeken, Robin van Schendel, Veronique Kalck, Marcel Tijsterman, Susan M Gasser
Histone H3 lysine 9 (H3K9) methylation is a conserved modification that generally represses transcription. In Caenorhabditis elegans it is enriched on silent tissue-specific genes and repetitive elements. In met-2 set-25 double mutants, which lack all H3K9 methylation (H3K9me), embryos differentiate normally, although mutant adults are sterile owing to extensive DNA-damage-driven apoptosis in the germ line. Transposons and simple repeats are derepressed in both germline and somatic tissues. This unprogrammed transcription correlates with increased rates of repeat-specific insertions and deletions, copy number variation, R loops and enhanced sensitivity to replication stress...
September 26, 2016: Nature Genetics
Isabel X Wang, Christopher Grunseich, Youree G Chung, Hojoong Kwak, Girish Ramrattan, Zhengwei Zhu, Vivian G Cheung
Alterations of RNA sequences and structures, such as those from editing and alternative splicing, result in two or more RNA transcripts from a DNA template. It was thought that in yeast, RNA editing only occurs in tRNAs. Here, we found that Saccharomyces cerevisiae have all 12 types of RNA-DNA sequence differences (RDDs) in the mRNA. We showed these sequence differences are propagated to proteins, as we identified peptides encoded by the RNA sequences in addition to those by the DNA sequences at RDD sites. RDDs are significantly enriched at regions with R-loops...
September 16, 2016: Genome Research
Patricia Richard, James L Manley
Aberrant R-loop structures are increasingly being realized to be an important contributor to human disease. R loops, which are mainly co-transcriptional, abundant RNA/DNA hybrids, form naturally and can indeed be beneficial for transcription regulation at certain loci. However, their unwanted persistence elsewhere or in particular situations can lead to DNA double-strand breaks, chromosome rearrangements and hypermutation, all sources of genomic instability. Mutations in genes involved in R-loop resolution or mutations leading to R-loop formation at specific genes affect the normal physiology of the cell...
September 3, 2016: Journal of Molecular Biology
Nimrat Chatterjee, Yunfu Lin, John H Wilson
Almost 20 incurable neurodegenerative disorders are caused by trinucleotide repeat (TNR) expansion beyond a certain threshold, with disease time of onset and severity positively correlating with repeat length. Typically, long TNRs display a bias toward further expansion and repeats continue to expand not only during germline transmissions from parents to offspring, but also remain highly unstable in somatic tissues of patients. Hence, understanding TNR instability mechanisms sheds light on underlying disease pathology...
May 2016: Postdoc Journal: a Journal of Postdoctoral Research and Postdoctoral Affairs
Megan L Hochstrasser, David W Taylor, Jack E Kornfeld, Eva Nogales, Jennifer A Doudna
Bacteria employ surveillance complexes guided by CRISPR (clustered, regularly interspaced, short palindromic repeats) RNAs (crRNAs) to target foreign nucleic acids for destruction. Although most type I and type III CRISPR systems require four or more distinct proteins to form multi-subunit surveillance complexes, the type I-C systems use just three proteins to achieve crRNA maturation and double-stranded DNA target recognition. We show that each protein plays multiple functional and structural roles: Cas5c cleaves pre-crRNAs and recruits Cas7 to position the RNA guide for DNA binding and unwinding by Cas8c...
September 1, 2016: Molecular Cell
Karan J Abraham, Janet N Y Chan, Jayesh S Salvi, Brandon Ho, Amanda Hall, Elva Vidya, Ru Guo, Samuel A Killackey, Nancy Liu, Jeffrey E Lee, Grant W Brown, Karim Mekhail
Dietary calorie restriction is a broadly acting intervention that extends the lifespan of various organisms from yeast to mammals. On another front, magnesium (Mg(2+)) is an essential biological metal critical to fundamental cellular processes and is commonly used as both a dietary supplement and treatment for some clinical conditions. If connections exist between calorie restriction and Mg(2+) is unknown. Here, we show that Mg(2+), acting alone or in response to dietary calorie restriction, allows eukaryotic cells to combat genome-destabilizing and lifespan-shortening accumulations of RNA-DNA hybrids, or R-loops...
October 14, 2016: Nucleic Acids Research
Caroline Townsend Stork, Michael Bocek, Madzia P Crossley, Julie Sollier, Lionel A Sanz, Frédéric Chédin, Tomek Swigut, Karlene A Cimprich
The hormone estrogen (E2) binds the estrogen receptor to promote transcription of E2-responsive genes in the breast and other tissues. E2 also has links to genomic instability, and elevated E2 levels are tied to breast cancer. Here, we show that E2 stimulation causes a rapid, global increase in the formation of R-loops, co-transcriptional RNA-DNA products, which in some instances have been linked to DNA damage. We show that E2-dependent R-loop formation and breast cancer rearrangements are highly enriched at E2-responsive genomic loci and that E2 induces DNA replication-dependent double-strand breaks (DSBs)...
2016: ELife
Vijay Kumar, Tara Kashav, Asimul Islam, Faizan Ahmad, Md Imtaiyaz Hassan
Hexanucleotide repeat expansions, (G4C2) in the C9orf72 gene are considered as the single most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). (G4C2), either as DNA or the transcribed RNA, can folds into unusual secondary structures, including G-quadruplex, R-loop, I-motif and hairpin. These structural polymorphism at both DNA and RNA levels were proposed to initiate molecular cascade leading to ALS/FTD. G-quadruplexes are composed of stacked G4 tetrads, held by hydrophobic bonds, and is highly stable secondary structure...
August 15, 2016: Neurochemistry International
Kaare Bjerregaard-Andersen, Ellen Østensen, John D Scott, Kjetil Taskén, Jens Preben Morth
A-kinase anchoring proteins (AKAPs) are a family of proteins that provide spatiotemporal resolution of protein kinase A (PKA) phosphorylation. In the myocardium, PKA and AKAP18γ/δ are found in complex with sarcoendoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca(2+) release and re-uptake. For this reason, AKAP18γ/δ presents an interesting drug target with therapeutic potential in cardiovascular disease...
August 2016: Acta Crystallographica. Section F, Structural Biology Communications
Peter C Stirling, Philip Hieter
DNA repair defects create cancer predisposition in humans by fostering a higher rate of mutations. While DNA repair is quite well characterized, recent studies have identified previously unrecognized relationships between DNA repair and R-loop-mediated genome instability. R-loops are three-stranded nucleic acid structures in which RNA binds to genomic DNA to displace a loop of single-stranded DNA. Mutations in homologous recombination, nucleotide excision repair, crosslink repair, and DNA damage checkpoints have all now been linked to formation and function of transcription-coupled R-loops...
July 22, 2016: Journal of Molecular Biology
Yongzhong Zhao, Won-Min Song, Fan Zhang, Ming-Ming Zhou, Weijia Zhang, Martin J Walsh, Bin Zhang
The genomic features and arising mechanisms of coding cancer somatic gene fusions (CSGFs) largely remain elusive. In this study, we show the gene origin stratification pattern of CSGF partners that fusion partners in human cancers are significantly enriched for genes with the gene age ofEuteleostomes and with the gene family age of Bilateria. GC skew (a measurement of G, C nucleotide content bias, (G-C)/(G+C)) is a useful measurement to indicate the DNA leading strand, lagging strand, replication origin, and replication terminal and DNA-RNA R-loop formation...
July 20, 2016: Oncotarget
Julio C Morales, Patricia Richard, Praveen L Patidar, Edward A Motea, Tuyen T Dang, James L Manley, David A Boothman
XRN2 is a 5'-3' exoribonuclease implicated in transcription termination. Here we demonstrate an unexpected role for XRN2 in the DNA damage response involving resolution of R-loop structures and prevention of DNA double-strand breaks (DSBs). We show that XRN2 undergoes DNA damage-inducible nuclear re-localization, co-localizing with 53BP1 and R loops, in a transcription and R-loop-dependent process. XRN2 loss leads to increased R loops, genomic instability, replication stress, DSBs and hypersensitivity of cells to various DNA damaging agents...
July 2016: PLoS Genetics
Merja Heinäniemi, Tapio Vuorenmaa, Susanna Teppo, Minna U Kaikkonen, Maria Bouvy-Liivrand, Juha Mehtonen, Henri Niskanen, Vasilios Zachariadis, Saara Laukkanen, Thomas Liuksiala, Kaisa Teittinen, Olli Lohi
Progression of malignancy to overt disease requires multiple genetic hits. Activation-induced deaminase (AID) can drive lymphomagenesis by generating off-target DNA breaks at loci that harbor highly active enhancers and display convergent transcription. The first active transcriptional profiles from acute lymphoblastic leukemia (ALL) patients acquired here reveal striking similarity at structural variation (SV) sites. Specific transcriptional features, namely convergent transcription and Pol2 stalling, were detected at breakpoints...
2016: ELife
Linda Koch
No abstract text is available yet for this article.
July 15, 2016: Nature Reviews. Genetics
Gokhan Akman, Radha Desai, Laura J Bailey, Takehiro Yasukawa, Ilaria Dalla Rosa, Romina Durigon, J Bradley Holmes, Chloe F Moss, Mara Mennuni, Henry Houlden, Robert J Crouch, Michael G Hanna, Robert D S Pitceathly, Antonella Spinazzola, Ian J Holt
The genetic information in mammalian mitochondrial DNA is densely packed; there are no introns and only one sizeable noncoding, or control, region containing key cis-elements for its replication and expression. Many molecules of mitochondrial DNA bear a third strand of DNA, known as "7S DNA," which forms a displacement (D-) loop in the control region. Here we show that many other molecules contain RNA as a third strand. The RNA of these R-loops maps to the control region of the mitochondrial DNA and is complementary to 7S DNA...
July 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Lionel A Sanz, Stella R Hartono, Yoong Wearn Lim, Sandra Steyaert, Aparna Rajpurkar, Paul A Ginno, Xiaoqin Xu, Frédéric Chédin
R-loops are three-stranded nucleic acid structures formed upon annealing of an RNA strand to one strand of duplex DNA. We profiled R-loops using a high-resolution, strand-specific methodology in human and mouse cell types. R-loops are prevalent, collectively occupying up to 5% of mammalian genomes. R-loop formation occurs over conserved genic hotspots such as promoter and terminator regions of poly(A)-dependent genes. In most cases, R-loops occur co-transcriptionally and undergo dynamic turnover. Detailed epigenomic profiling revealed that R-loops associate with specific chromatin signatures...
July 7, 2016: Molecular Cell
Sushma Krishnan, Anushya Petchiappan, Albel Singh, Apoorva Bhatt, Dipankar Chatterji
Persistent R-loops lead to replicative stress due to RNA polymerase stalling and DNA damage. RNase H enzymes facilitate the organisms to survive in the hostile condition by removing these R-loops. MS_RHII-RSD was previously identified to be the second (p)ppGpp synthetase in Mycobacterium smegmatis. The unique presence of an additional RNase HII domain raises an important question regarding the significance of this bifunctional protein. In this report, we demonstrate its ability to hydrolyze R-loops in Escherichia coli exposed to UV stress...
October 2016: Molecular Microbiology
Thomas G Fazzio
Hybridization of RNA to its template DNA strand during transcription induces formation of R-loops-RNA:DNA hybrids with unpaired non-template DNA strands. Although unresolved R-loops can be detrimental, some R-loops contribute to regulation of chromatin structure. Consequently, R-loops help regulate gene expression and play important roles in numerous cellular processes.
August 7, 2016: Transcription
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