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Andrew G L Douglas
A hexanucleotide repeat expansion in the first intron/promoter region of C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both sense and antisense transcripts exist at the C9orf72 locus but the function of the antisense lncRNA is unknown. RNA toxicity of the transcribed repeat expansion has been implicated in the pathogenesis of C9orf72 -related ALS/FTD, not only through direct sequestration of important RNA binding proteins but also indirectly through non-ATG dependent translation into dipeptide repeats...
December 2018: Non-Coding RNA Research
Nodar Makharashvili, Sucheta Arora, Yizhi Yin, Qiong Fu, Xuemei Wen, Ji-Hoon Lee, Chung-Hsuan Kao, Justin Wc Leung, Kyle M Miller, Tanya T Paull
The Sae2/CtIP protein is required for efficient processing of DNA double-strand breaks that initiate homologous recombination in eukaryotic cells. Sae2/CtIP is also important for survival of single-stranded Top1-induced lesions and CtIP is known to associate directly with transcription-associated complexes in mammalian cells. Here we investigate the role of Sae2/CtIP at single-strand lesions in budding yeast and in human cells and find that depletion of Sae2/CtIP promotes the accumulation of stalled RNA polymerase and RNA-DNA hybrids at sites of highly expressed genes...
December 7, 2018: ELife
Stefano Stella, Pablo Mesa, Johannes Thomsen, Bijoya Paul, Pablo Alcón, Simon B Jensen, Bhargav Saligram, Matias E Moses, Nikos S Hatzakis, Guillermo Montoya
Cas12a, also known as Cpf1, is a type V-A CRISPR-Cas RNA-guided endonuclease that is used for genome editing based on its ability to generate specific dsDNA breaks. Here, we show cryo-EM structures of intermediates of the cleavage reaction, thus visualizing three protein regions that sense the crRNA-DNA hybrid assembly triggering the catalytic activation of Cas12a. Single-molecule FRET provides the thermodynamics and kinetics of the conformational activation leading to phosphodiester bond hydrolysis. These findings illustrate why Cas12a cuts its target DNA and unleashes unspecific cleavage activity, degrading ssDNA molecules after activation...
November 15, 2018: Cell
Saša Šviković, Alastair Crisp, Sue Mei Tan-Wong, Thomas A Guilliam, Aidan J Doherty, Nicholas J Proudfoot, Guillaume Guilbaud, Julian E Sale
During DNA replication, conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three-stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single-stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here, we show in vivo how R-loop formation drives a short purine-rich repeat, (GAA)10 , to become a replication impediment that engages the repriming activity of the primase-polymerase PrimPol...
November 26, 2018: EMBO Journal
Jie Chen, Xinggui Shen, Sibile Pardue, Andrew T Meram, Saranya Rajendran, Ghali E Ghali, Christopher G Kevil, Rodney E Shackelford
The ataxia telangiectasia-mutated and Rad3-related (ATR) serine/threonine kinase plays a central role in the repair of replication-associated DNA damage, the maintenance of S and G2/M-phase genomic stability, and the promotion of faithful mitotic chromosomal segregation. A number of stimuli activate ATR, including persistent single-stranded DNA at stalled replication folks, R loop formation, hypoxia, ultraviolet light, and oxidative stress, leading to ATR-mediated protein phosphorylation. Recently, hydrogen sulfide (H2 S), an endogenous gasotransmitter, has been found to regulate multiple cellular processes through complex redox reactions under similar cell stress environments...
November 13, 2018: DNA Repair
Annie S Tam, Tianna S Sihota, Karissa L Milbury, Anni Zhang, Veena Mathew, Peter C Stirling
RNA processing mutants have been broadly implicated in genome stability but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability...
November 21, 2018: Molecular Biology of the Cell
Takayuki Nojima, Michael Tellier, Jonathan Foxwell, Claudia Ribeiro de Almeida, Sue Mei Tan-Wong, Somdutta Dhir, Gwendal Dujardin, Ashish Dhir, Shona Murphy, Nick J Proudfoot
Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription...
November 8, 2018: Molecular Cell
Éva Hegedüs, Endre Kókai, Péter Nánási, László Imre, László Halász, Rozenn Jossé, Zsuzsa Antunovics, Martin R Webb, Aziz El Hage, Yves Pommier, Lóránt Székvölgyi, Viktor Dombrádi, Gábor Szabó
Molecular combing and gel electrophoretic studies revealed endogenous nicks with free 3'OH ends at ∼100 kb intervals in the genomic DNA (gDNA) of unperturbed and G1-synchronized Saccharomyces cerevisiae cells. Analysis of the distribution of endogenous nicks by Nick ChIP-chip indicated that these breaks accumulated at active RNA polymerase II (RNAP II) promoters, reminiscent of the promoter-proximal transient DNA breaks of higher eukaryotes. Similar periodicity of endogenous nicks was found within the ribosomal rDNA cluster, involving every ∼10th of the tandemly repeated 9...
November 16, 2018: Nucleic Acids Research
Yusuke Okamoto, Masako Abe, Akiko Itaya, Junya Tomida, Masamichi Ishiai, Akifumi Takaori-Kondo, Masato Taoka, Toshiaki Isobe, Minoru Takata
R-loops, which consist of DNA : RNA hybrids and displaced single-strand DNA, are a major threat to genome stability. We have previously reported that a key Fanconi anemia protein, FANCD2, accumulates on large fragile genes during mild replication stress in a manner depending on R-loops. In this study, we found that FANCD2 suppresses R-loop levels. Furthermore, we identified FANCD2 interactions with RNA processing factors, including hnRNP U and DDX47. Our data suggest that FANCD2, which accumulates with R-loops in chromatin, recruits these factors and thereby promotes efficient processing of long RNA transcripts...
November 15, 2018: FEBS Journal
Diana Zheglo, Lena M Brueckner, Olga Sepman, Elisa M Wecht, Ekaterina Kuligina, Evgenij Suspitsin, Evgenij Imyanitov, Larissa Savelyeva
Common fragile sites (cFSs) represent parts of the normal chromosome structure susceptible to breakage under replication stress. Although only a small number of cFSs have been molecularly characterised, genomic damage of cFS genes appears to be critical for the development of various human diseases. In this study, we fine mapped the location of FRA14B and showed that the fragile region spans 765 kb at 14q23.3, containing the large gephyrin (GPHN) gene. The FRA14B sequence is enriched in perfect A/T>24 stretches and R-loop forming sequences (RLFS), and harbours a large palindromic motif in the core region...
November 8, 2018: Genes, Chromosomes & Cancer
Manar Abu Diab, Hagar Mor-Shaked, Eliora Cohen, Yaara Cohen-Hadad, Oren Ram, Silvina Epsztejn-Litman, Rachel Eiges
Pathological mutations involving noncoding microsatellite repeats are typically located near promoters in CpG islands and are coupled with extensive repeat instability when sufficiently long. What causes these regions to be prone to repeat instability is not fully understood. There is a general consensus that instability results from the induction of unusual structures in the DNA by the repeats as a consequence of mispairing between complementary strands. In addition, there is some evidence that repeat instability is mediated by RNA transcription through the formation of three-stranded nucleic structures composed of persistent DNA:RNA hybrids, concomitant with single strand DNA displacements (R-loops)...
November 5, 2018: Genetics
Michelle Debatisse, Filippo Rosselli
The replication process should be as faithful as possible in order to minimize mutations but some regions of the genome, named fragile sites, are hypersensitive to replication stress and often involved in the generation of gross chromosome rearrangements. Common fragile sites (CFSs) are a type of fragile sites that nest within very large genes and display cell-type-dependent instability. Fragile or not, large genes replicate late in S-phase but their complete replication is specifically delayed upon replication fork slowing, only when they are transcribed...
November 1, 2018: Genes, Chromosomes & Cancer
Liangzhen Zheng, Jiahai Shi, Yuguang Mu
CRISPR-Cas9, a powerful genome editing tool, has widely been applied in biological fields. Since the discovery of CRISPR-Cas9 as an adaptive immune system, it has been gradually modified to perform precise genome editing in eukaryotic cells by creating double-strand breaks. Although it is robust and efficient, the current CRISPR-Cas9 system faces a major flaw: off-target effects, which are not well understood. Several Cas9 mutants show significant improvement, with very low off-target effects; however, they also show relatively lower cleavage efficiency for on-target sequences...
November 7, 2018: Physical Chemistry Chemical Physics: PCCP
Tabish Hussain, Bin Liu, Morgan S Shrock, Terence Williams, C Marcelo Aldaz
WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1-q23.2 and containing FRA16D, the second most common chromosomal fragile site (CFS). FRA16D is a hotspot of genomic instability, prone to breakage and for causing germline and somatic copy number variants (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma...
October 23, 2018: Genes, Chromosomes & Cancer
Prasun Chakraborty, Jeffrey T J Huang, Kevin Hiom
R-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased R-loops cause replication stress and chromosome fragility and have been associated with diseases such as neurodegeneration and cancer. Although excessive R-loops are a feature of cells that are defective in RNA processing, what causes them to form is unclear. Here, we demonstrate that DHX9 (RNA helicase A) promotes the formation of pathological and non-pathological R-loops...
October 19, 2018: Nature Communications
Anna Konopka, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 ( C9orf72 ) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats...
October 12, 2018: International Journal of Molecular Sciences
Emma Briggs, Graham Hamilton, Kathryn Crouch, Craig Lapsley, Richard McCulloch
R-loops are stable RNA-DNA hybrids that have been implicated in transcription initiation and termination, as well as in telomere maintenance, chromatin formation, and genome replication and instability. RNA Polymerase (Pol) II transcription in the protozoan parasite Trypanosoma brucei is highly unusual: virtually all genes are co-transcribed from multigene transcription units, with mRNAs generated by linked trans-splicing and polyadenylation, and transcription initiation sites display no conserved promoter motifs...
October 10, 2018: Nucleic Acids Research
Sonia Silva, Lola P Camino, Andrés Aguilera
R loops are nucleic acid structures comprising an DNA-RNA hybrid and a displaced single-stranded DNA. These structures may occur transiently during transcription, playing essential biological functions. However, persistent R loops may become pathological as they are important drivers of genome instability and have been associated with human diseases. The mitochondrial degradosome is a functionally conserved complex from bacteria to human mitochondria. It is composed of the ATP-dependent RNA and DNA helicase SUV3 and the PNPase ribonuclease, playing a central role in mitochondrial RNA surveillance and degradation...
October 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yaqun Teng, Tribhuwan Yadav, Meihan Duan, Jun Tan, Yufei Xiang, Boya Gao, Jianquan Xu, Zhuobin Liang, Yang Liu, Satoshi Nakajima, Yi Shi, Arthur S Levine, Lee Zou, Li Lan
Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain...
October 8, 2018: Nature Communications
(no author information available yet)
RAD52-mediated processing of R-loops initiates high-fidelity DNA repair in actively transcribed regions.
November 2018: Cancer Discovery
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