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https://www.readbyqxmd.com/read/28318821/snf2-family-protein-fft3-suppresses-nucleosome-turnover-to-promote-epigenetic-inheritance-and-proper-replication
#1
Nitika Taneja, Martin Zofall, Vanivilasini Balachandran, Gobi Thillainadesan, Tomoyasu Sugiyama, David Wheeler, Ming Zhou, Shiv I S Grewal
Heterochromatin can be epigenetically inherited in cis, leading to stable gene silencing. However, the mechanisms underlying heterochromatin inheritance remain unclear. Here, we identify Fft3, a fission yeast homolog of the mammalian SMARCAD1 SNF2 chromatin remodeler, as a factor uniquely required for heterochromatin inheritance, rather than for de novo assembly. Importantly, we find that Fft3 suppresses turnover of histones at heterochromatic loci to facilitate epigenetic transmission of heterochromatin in cycling cells...
March 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28314779/an-atr-dependent-function-for-the-ddx19-rna-helicase-in-nuclear-r-loop-metabolism
#2
Dana Hodroj, Bénédicte Recolin, Kamar Serhal, Susan Martinez, Nikolay Tsanov, Raghida Abou Merhi, Domenico Maiorano
Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops...
March 17, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28273945/crispr-cas9-cleavage-efficiency-correlates-strongly-with-target-sgrna-folding-stability-from-physical-mechanism-to-off-target-assessment
#3
Xiaojun Xu, Dongsheng Duan, Shi-Jie Chen
The CRISPR/Cas9 complex, a bacterial immune response system, has been widely adopted for RNA-guided genome editing and transcription regulation in applications such as targeted genome modification and site-directed mutagenesis. However, the physical basis for its target specificity is not fully understood. In this study, based on a statistical mechanical analysis for the whole ensemble of sgRNA-target complex conformations, we identify a strong correlation between Cas9 cleavage efficiency and the stability of the DNA-RNA (R-loop) complex structures, with a Pearson correlation coefficient ranging from 0...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28270613/smn-deficiency-in-severe-models-of-spinal-muscular-atrophy-causes-widespread-intron-retention-and-dna-damage
#4
Mohini Jangi, Christina Fleet, Patrick Cullen, Shipra V Gupta, Shila Mekhoubad, Eric Chiao, Norm Allaire, C Frank Bennett, Frank Rigo, Adrian R Krainer, Jessica A Hurt, John P Carulli, John F Staropoli
Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28270450/ssb1-and-ssb2-cooperate-to-regulate-mouse-hematopoietic-stem-and-progenitor-cells-by-resolving-replicative-stress
#5
Wei Shi, Therese Vu, Didier Boucher, Anna Biernacka, Jules Nde, Raj K Pandita, Jasmin Straube, Glen M Boyle, Fares Al-Ejeh, Purba Nag, Jessie Jeffery, Janelle L Harris, Amanda L Bain, Marta Grzelak, Magdalena Skrzypczak, Abhishek Mitra, Norbert Dojer, Nicola Crosetto, Nicole Cloonan, Olivier J Becherel, John Finnie, Jeffrey R Skaar, Carl R Walkley, Tej K Pandita, Maga Rowicka, Krzysztof Ginalski, Steven W Lane, Kum Kum Khanna
Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The two single-stranded DNA binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however their overlapping roles during normal physiology are incompletely understood. We generated mice where both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, while conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of Ssb1 or Ssb2 Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double strand breaks (DSBs) enriched at Ssb binding regions and CpG islands, together with the accumulation of R-loops and cytosolic ssDNA...
March 7, 2017: Blood
https://www.readbyqxmd.com/read/28268090/both-r-loop-removal-and-ribonucleotide-excision-repair-activities-of-rnase-h2-contribute-substantially-to-chromosome-stability
#6
Deborah A Cornelio, Hailey N C Sedam, Jessica A Ferrarezi, Nadia M V Sampaio, Juan Lucas Argueso
Cells carrying deletions of genes encoding H-class ribonucleases display elevated rates of chromosome instability. The role of these enzymes is to remove RNA-DNA associations including persistent mRNA-DNA hybrids (R-loops) formed during transcription, and ribonucleotides incorporated into DNA during replication. RNases H1 and H2 can degrade the RNA component of R-loops, but only RNase H2 can initiate accurate ribonucleotide excision repair (RER). In order to examine the specific contributions of these activities to chromosome stability, we measured rates of loss-of-heterozygosity (LOH) in diploid Saccharomyces cerevisiae yeast strains carrying the rnh201-RED separation-of-function allele, encoding a version of RNase H2 that is RER-defective, but partly retains its other activity...
February 20, 2017: DNA Repair
https://www.readbyqxmd.com/read/28257700/functions-of-replication-protein-a-as-a-sensor-of-r-loops-and-a-regulator-of-rnaseh1
#7
Hai Dang Nguyen, Tribhuwan Yadav, Sumanprava Giri, Borja Saez, Timothy A Graubert, Lee Zou
R loop, a transcription intermediate containing RNA:DNA hybrids and displaced single-stranded DNA (ssDNA), has emerged as a major source of genomic instability. RNaseH1, which cleaves the RNA in RNA:DNA hybrids, plays an important role in R loop suppression. Here we show that replication protein A (RPA), an ssDNA-binding protein, interacts with RNaseH1 and colocalizes with both RNaseH1 and R loops in cells. In vitro, purified RPA directly enhances the association of RNaseH1 with RNA:DNA hybrids and stimulates the activity of RNaseH1 on R loops...
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28203566/increased-spontaneous-recombination-in-rnase-h2-deficient-cells-arises-from-multiple-contiguous-rnmps-and-not-from-single-rnmp-residues-incorporated-by-dna-polymerase-epsilon
#8
Anastasiya Epshtein, Catherine J Potenski, Hannah L Klein
Ribonucleotides can become embedded in DNA from insertion by DNA polymerases, failure to remove Okazaki fragment primers, R-loops that can prime replication, and RNA/cDNA-mediated recombination. RNA:DNA hybrids are removed by RNase H enzymes. Single rNMPs in DNA are removed by RNase H2 and if they remain on the leading strand, can lead to mutagenesis in a Top1-dependent pathway. rNMPs in DNA can also stimulate genome instability, among which are homologous recombination gene conversion events. We previously found that, similar to the rNMP-stimulated mutagenesis, rNMP-stimulated recombination was also Top1-dependent...
June 2016: Microbial Cell
https://www.readbyqxmd.com/read/28098815/replication-fork-protection-factors-controlling-r-loop-bypass-and-suppression
#9
REVIEW
Emily Yun-Chia Chang, Peter C Stirling
Replication-transcription conflicts have been a well-studied source of genome instability for many years and have frequently been linked to defects in RNA processing. However, recent characterization of replication fork-associated proteins has revealed that defects in fork protection can directly or indirectly stabilize R-loop structures in the genome and promote transcription-replication conflicts that lead to genome instability. Defects in essential DNA replication-associated activities like topoisomerase, or the minichromosome maintenance (MCM) helicase complex, as well as fork-associated protection factors like the Fanconi anemia pathway, both appear to mitigate transcription-replication conflicts...
January 14, 2017: Genes
https://www.readbyqxmd.com/read/28076779/transcription-dynamics-prevent-rna-mediated-genomic-instability-through-srpk2-dependent-ddx23-phosphorylation
#10
Sreerama Chaitanya Sridhara, Sílvia Carvalho, Ana Rita Grosso, Lina Marcela Gallego-Paez, Maria Carmo-Fonseca, Sérgio Fernandes de Almeida
Genomic instability is frequently caused by nucleic acid structures termed R-loops that are formed during transcription. Despite their harmful potential, mechanisms that sense, signal, and suppress these structures remain elusive. Here, we report that oscillations in transcription dynamics are a major sensor of R-loops. We show that pausing of RNA polymerase II (RNA Pol II) initiates a signaling cascade whereby the serine/arginine protein kinase 2 (SRPK2) phosphorylates the DDX23 helicase, culminating in the suppression of R-loops...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28065739/r-loop-depletion-by-over-expressed-rnase-h1-in-mouse-b-cells-increases-activation-induced-deaminase-access-to-the-transcribed-strand-without-altering-frequency-of-isotype-switching
#11
Robert W Maul, Hyongi Chon, Kiran Sakhuja, Susana M Cerritelli, Lina A Gugliotti, Patricia J Gearhart, Robert J Crouch
R-loops, three-strand structures consisting of mRNA hybridized to the complementary DNA and a single-stranded DNA loop, are formed in switch regions on the heavy-chain immunoglobulin locus. To determine if R-loops have a direct effect on any of the steps involved in isotype switching, we generated a transgenic mouse that over-expressed RNase H1, an enzyme that cleaves the RNA of RNA/DNA hybrids in B cells. R-loops in the switch μ region were depleted by 70% in ex vivo activated splenic B cells. Frequencies of isotype switching to IgG1, IgG2b, IgG2c, and IgG3 were the same as C57BL/6 control cells...
January 6, 2017: Journal of Molecular Biology
https://www.readbyqxmd.com/read/28062037/single-molecule-insight-into-target-recognition-by-crispr-cas-complexes
#12
M Rutkauskas, A Krivoy, M D Szczelkun, C Rouillon, R Seidel
Ribonucleoprotein (RNP) complexes from CRISPR-Cas systems have attracted enormous interest since they can be easily and flexibly reprogrammed to target any desired locus for genome engineering and gene regulation applications. Basis for the programmability is a short RNA (crRNA) inside these complexes that recognizes the target nucleic acid by base pairing. For CRISPR-Cas systems that target double-stranded DNA this results in local DNA unwinding and formation of a so-called R-loop structure. Here we provide an overview how this target recognition mechanism can be dissected in great detail at the level of a single molecule...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/27991914/the-spliceosome-u2-snrnp-factors-promote-genome-stability-through-distinct-mechanisms-transcription-of-repair-factors-and-r-loop-processing
#13
M Tanikawa, K Sanjiv, T Helleday, P Herr, O Mortusewicz
Recent whole-exome sequencing of malignancies have detected recurrent somatic mutations in U2 small nuclear ribonucleoprotein complex (snRNP) components of the spliceosome. These factors have also been identified as novel players in the DNA-damage response (DDR) in several genome-wide screens and proteomic analysis. Although accumulating evidence implies that the spliceosome has an important role in genome stability and is an emerging hallmark of cancer, its precise role in DNA repair still remains elusive...
December 19, 2016: Oncogenesis
https://www.readbyqxmd.com/read/27991904/pif1-family-helicases-cooperatively-suppress-widespread-replication-fork-arrest-at-trna-genes
#14
Joseph S Osmundson, Jayashree Kumar, Rani Yeung, Duncan J Smith
Saccharomyces cerevisiae expresses two Pif1-family helicases-Pif1 and Rrm3-which have been reported to play distinct roles in numerous nuclear processes. Here, we systematically characterized the roles of Pif1 helicases in replisome progression and lagging-strand synthesis in S. cerevisiae. We demonstrate that either Pif1 or Rrm3 redundantly stimulates strand displacement by DNA polymerase δ during lagging-strand synthesis. By analyzing replisome mobility in pif1 and rrm3 mutants, we show that Rrm3, with a partially redundant contribution from Pif1, suppresses widespread terminal arrest of the replisome at tRNA genes...
February 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27974207/dna-replication-origins-in-immunoglobulin-switch-regions-regulate-class-switch-recombination-in-an-r-loop-dependent-manner
#15
Eva-Maria Wiedemann, Mihaela Peycheva, Rushad Pavri
Class switch recombination (CSR) at the immunoglobulin heavy chain (IgH) locus generates antibody isotypes. CSR depends on double-strand breaks (DSBs) induced by activation-induced cytidine deaminase (AID). Although DSB formation and repair machineries are active in G1 phase, efficient CSR is dependent on cell proliferation and S phase entry; however, the underlying mechanisms are obscure. Here, we show that efficient CSR requires the replicative helicase, the Mcm complex. Mcm proteins are enriched at IgH switch regions during CSR, leading to assembly of facultative replication origins that require Mcm helicase function for productive CSR...
December 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27938663/rnase-h-enables-efficient-repair-of-r-loop-induced-dna-damage
#16
Jeremy D Amon, Douglas Koshland
R-loops, three-stranded structures that form when transcripts hybridize to chromosomal DNA, are potent agents of genome instability. This instability has been explained by the ability of R-loops to induce DNA damage. Here, we show that persistent R-loops also compromise DNA repair. Depleting endogenous RNase H activity impairs R-loop removal in Saccharomyces cerevisiae, causing DNA damage that occurs preferentially in the repetitive ribosomal DNA locus (rDNA). We analyzed the repair kinetics of this damage and identified mutants that modulate repair...
December 10, 2016: ELife
https://www.readbyqxmd.com/read/27899586/r-loopdb-a-database-for-r-loop-forming-sequences-rlfs-and-r-loops
#17
Piroon Jenjaroenpun, Thidathip Wongsurawat, Sawannee Sutheeworapong, Vladimir A Kuznetsov
R-loopDB (http://rloop.bii.a-star.edu.sg) was originally constructed as a collection of computationally predicted R-loop forming sequences (RLFSs) in the human genic regions. The renewed R-loopDB provides updates, improvements and new options, including access to recent experimental data. It includes genome-scale prediction of RLFSs for humans, six other animals and yeast. Using the extended quantitative model of RLFSs (QmRLFS), we significantly increased the number of RLFSs predicted in the human genes and identified RLFSs in other organism genomes...
January 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27863397/targeting-gli-by-gant61-involves-mechanisms-dependent-on-inhibition-of-both-transcription-and-dna-licensing
#18
Ruowen Zhang, Jiahui Wu, Sylvain Ferrandon, Katie J Glowacki, Janet A Houghton
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27851891/traveling-rocky-roads-the-consequences-of-transcription-blocking-dna-lesions-on-rna-polymerase-ii
#19
REVIEW
Barbara Steurer, Jurgen A Marteijn
The faithful transcription of eukaryotic genes by RNA polymerase II (RNAP2) is crucial for proper cell function and tissue homeostasis. However, transcription-blocking DNA lesions of both an endogenous and environmental origin continuously challenge the progression of elongating RNAP2. The stalling of RNAP2 on a transcription-blocking lesion triggers a series of highly regulated events, including RNAP2 processing to make the lesion accessible for DNA repair, R-loop-mediated DNA damage signaling, and the initiation of transcription-coupled DNA repair...
November 13, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27849576/two-familial-als-proteins-function-in-prevention-repair-of-transcription-associated-dna-damage
#20
Sarah J Hill, Daniel A Mordes, Lisa A Cameron, Donna S Neuberg, Serena Landini, Kevin Eggan, David M Livingston
Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
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