Top 10 Biorxiv Papers Today in Molecular Biology


2.009 Mikeys
#1. Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1
Hideo Nishitani, Akiyo Hayashi, Nickolaos Nikiforos Giakoumakis, Tatjana Heidebrecht, Takashi Ishii, Andreas Panagopoulos, Christophe Caillat, Michiyo Takahara, Richard G Hibbert, Naohiro Suenaga, Magda Stadnik-Spiewak, Tatsuro Takahashi, Yasushi Shiomi, Stavros Taraviras, Eleonore von Castelmur, Zoi Lygerou, Anastassis Perrakis
The CRL4Cdt2 ubiquitin ligase complex is an essential regulator of cell-cycle progression and genome stability, ubiquitinating substrates such as p21, Set8 and Cdt1, via a display of substrate degrons on PCNA. Here, we examine the hierarchy of the ligase and substrate recruitment kinetics onto PCNA at sites of DNA replication. We demonstrate that the C-terminal end of Cdt2 bears a PCNA interaction protein motif (PIP box, Cdt2PIP), which is necessary and sufficient for binding of Cdt2 to PCNA. Cdt2PIP binds PCNA directly with high affinity, two orders of magnitude tighter than the PIP box of Cdt1. X-ray crystallographic structures of PCNA bound to Cdt2PIP and Cdt1PIP show that the peptides occupy all three binding sites of the trimeric PCNA ring. Mutating Cdt2PIP weakens the interaction with PCNA, rendering CRL4Cdt2 less effective in Cdt1 ubiquitination and leading to defects in Cdt1 degradation. The molecular mechanism we present suggests a new paradigm for bringing substrates to the CRL4-type ligase, where the substrate receptor...
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biorxivpreprint: Direct binding of Cdt2 to PCNA is important for targeting the CRL4Cdt2 E3 ligase activity to Cdt1 https://t.co/9TADENbF91 #bioRxiv
TassosPerrakis: What does it take to publish results that present a molecular mechanism different than the one described in a Cell paper? Read about it at: https://t.co/E5ecBxxlsa
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Sample Sizes : [3, 200]
Authors: 17
Total Words: 15935
Unqiue Words: 3910

2.003 Mikeys
#2. Identification of proteins involved in Trypanosoma brucei DNA replication fork dynamics using nascent DNA proteomics
Maria Rocha-Granados, Yahaira Bermudez, Garvin Dodard, Anthula Vandoros, Arthur Gunzl, Michele Klingbeil
DNA replication, transcription and chromatin remodeling are coordinated to ensure accurate duplication of genetic and epigenetic information. In regard to DNA replication, trypanosomatid parasites such as Trypanosoma brucei display unusual properties including significantly fewer origins of replication than model eukaryotes, a highly divergent Origin Replication Complex (ORC), and an apparent lack of several replication factor homologs. Although recent studies in T. brucei indicate functional links among DNA replication, transcription, and antigenic variation, the underlying mechanisms remain unknown. Here, we adapted an unbiased technology for the identification of replication fork proteins called iPOND (isolation of proteins on nascent DNA) to T. brucei, its first application to a parasite system. This led to the mass spectrometric identification of core replication machinery and of proteins associated with transcription, chromatin organization, and DNA repair that were enriched in the vicinity of an unperturbed active...
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biorxivpreprint: Identification of proteins involved in Trypanosoma brucei DNA replication fork dynamics using nascent DNA proteomics https://t.co/voFBbVUrlf #bioRxiv
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Sample Sizes : None.
Authors: 6
Total Words: 17614
Unqiue Words: 6221

1.998 Mikeys
#3. Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells
Yoshiki HIGASHIJIMA, Yusuke MATSUI, Teppei SHIMAMURA, Shuichi TSUTSUMI, Ryo NAKAKI, Yohei ABE, Verena M LINK, Mizuko OSAKA, Masayuki YOSHIDA, Ryo WATANABE, Toshihiro TANAKA, Akashi TAGUCHI, Mai MIURA, Tsuyoshi INOUE, Masaomi NANGAKU, Hiroshi KIMURA, Tetsushi FURUKAWA, Hiroyuki ABURATANI, Youichiro WADA, Christopher K GLASS, Yasuharu KANKI
Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are generally linked to gene repression. However, the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. We found that tumor necrosis factor (TNF)-α rapidly induces the co-occupancy of lysine demethylases 7A (KDM7A) and 6A (UTX) with nuclear factor kappa-B (NF-κB) recruited elements in human endothelial cells. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and both are required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods demonstrated increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A- and UTX-recruitment. Simultaneous inhibition of KDM7A and UTX significantly reduced leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by...
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Sample Sizes : [3, 3, 3]
Authors: 21
Total Words: 25977
Unqiue Words: 6108

1.996 Mikeys
#4. An integrative study on ribonucleoprotein condensates identifies scaffolding RNAs and reveals a new player in Fragile X-associated Tremor/Ataxia Syndrome
Fernando Cid-Samper, Iona Gelabert-Baldrich, Benjamin Lang, Nieves Lorenzo-Gotor, Riccardo Delli Ponti, Lies-Anne WFM Severijnen, Benedetta Bolognesi, Ellen Gelpi, Renate K. Hukema-Felten, Teresa Botta-Orfila, Gian Gaetano Tartaglia
Recent evidence indicates that specific RNAs promote formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs). We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly-contacted RNAs are highly structured, have long untranslated regions (UTRs) and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3' UTR that harbors CGG expansions implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model we validated TRA2A-FRM1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post mortem human samples. Our integrative study identifies key components of ribonucleoprotein aggregates, providing...
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Sample Sizes : None.
Authors: 11
Total Words: 11038
Unqiue Words: 3399

0.0 Mikeys
#5. Functional genomics and programmed genome editing of omega-1 of the blood fluke Schistosoma mansoni
Wannaporn Ittiprasert, Victoria H Mann, Shannon E Karinshak, Apisit Chaidee, Toshihiko Tanno, Chutima Kumkhaek, Pannathee Prangtaworn, Margaret Mentink-Kane, Geetha Sankaranarayan, Avril Coghlan, Christina J Cochran, Gabriel Rinaldi, Patrick Driguez, Nancy Holroyd, Alan Tracey, Cornelis H Hokke, Bart Everts, Karl F Hoffmann, Matthew Berriman, Paul J Brindley
Soluble egg antigen (SEA) and excretory-secretory (ES) products of the egg of Schistosoma mansoni contain a glycosylated T2 family ribonuclease termed omega-1 (ω1). Following release from the egg ω1 instructs antigen presenting cells to induce naïve CD4+ T cells to mature into T helper 2 effectors that, in turn, establish the Th2 immunological phenotype characteristic of schistosomiasis. Here schistosome eggs were either transiently exposed to recombinant Cas9 complexed with a synthetic guide RNA (sgRNA) of 20 nt complementary to exon 1 of ω1 by electroporation or transduced with pseudotyped lentivirus encoding Cas9 and this sgRNA. Subsequently some eggs also were transduced with a single stranded oligodeoxynucleotide donor transgene that coded for six stop codons, flanked by 50 nt-long 5′- and 3′-homology arms matching the predicted Cas9-catalyzed double stranded break (DSB) within ω1. CRISPResso analysis of amplicons spanning the predicted DSB revealed ~6% of the reads (total reads 2×61620×106) were mutated by insertions,...
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Sample Sizes : None.
Authors: 20
Total Words: 14501
Unqiue Words: 5404

0.0 Mikeys
#6. The Nonstructural Proteins 3 And 5 From Flavivirus Modulate Nuclear-Cytoplasmic Transport And Innate Immune Response Targeting Nuclear Proteins
Margot Cervantes-Salazar, Ana L Gutierrez-Escolano, Jose M Reyes-Ruiz, Rosa M del Angel
Viruses hijack cellular proteins and components to be replicated in the host cell and to evade the immune response. Although flaviviruses have a cytoplasmic replicative cycle, some viral proteins such as the capsid (C) and the RNA dependent RNA polymerase, NS5, can reach the nucleus of the infected cells. Considering the important roles of NS5 in viral replication and in the control of the immune response, and its striking presence in the nucleus, the possible functions of this protein in some mechanisms orchestrated by the nucleus was analyzed. We isolated and identified nuclear proteins that interact with NS5; one of them, the DEAD-box RNA helicase DDX5 is relocated to the cytoplasm and degraded during infection with DENV, which correlates with its function in IFN dependent response. Since DDX5 and many other proteins are relocated from the nucleus to the cytoplasm during flavivirus infection, the integrity and function of the main regulator of the nuclear-cytoplasmic transport, the nuclear pore complex (NPC) was evaluated. We...
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Sample Sizes : None.
Authors: 4
Total Words: 15423
Unqiue Words: 3404

0.0 Mikeys
#7. Dynamics of age-related catastrophic mitotic failures and recovery in yeast
Matthew M Crane, Adam E Russell, Brent J Schafer, Mung Gi Hong, Joslyn E Goings, Kenneth L Chen, Ben W Blue, Matt Kaeberlein
Genome instability is a hallmark of aging and contributes to age-related disorders such as progeria, cancer, and Alzheimer's disease. Cell cycle checkpoints have generally been studied in young cells and animals where genomic instability is low. Here, we use single-cell imaging to study consequences of increased genomic instability during aging, and identify striking age-associated genome missegregation events where the majority of chromatin is mistakenly sent to the daughter cell. A transient cell cycle arrest that can persist for many hours, as cells engage a retrograde transport mechanism to return chromosomes to the mother cell, accompanies this breakdown in mitotic fidelity. The repetitive ribosomal DNA (rDNA) has been previously identified as being highly vulnerable to age-related replication stress, and we present several lines of evidence supporting a model whereby expansion of rDNA during aging results in nucleolar breakdown and competition for limited nucleosomes, thereby increasing risk of catastrophic genome missegregation.
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crane_mm: Really excited to share my new paper "Dynamics of age-related catastrophic mitotic failures and recovery in yeast". Something I've been working on for the past few years in the @mkaeberlein lab. Thread (1/n) with lots of movies https://t.co/2IiogTcHAr
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Sample Sizes : [359, 2697, 466, 3146, 459, 481, 587, 93, 2513, 298]
Authors: 8
Total Words: 16721
Unqiue Words: 4613

0.0 Mikeys
#8. Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice
Matthew Simon, Michael van Meter, Julia Ablaeva, Zhonghe Ke, Raul S Gonzalez, Taketo Taguchi, Marco De Cecco, Katerina I Leonova, Valeria Kogan, Stephen L Helfand, Nicola Neretti, Asael Roichman, Haim Y Cohen, Marina Antoch, Andrei Gudkov, John M Sedivy, Andrei Seluanov, Vera Gorbunova
Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6 deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA which triggers massive type I interferon response via activation of cGAS. Remarkably, nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number and type I interferons were elevated in the wild type aged mice. As sterile inflammation is a hallmark of aging we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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biorxivpreprint: Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice https://t.co/2VL4ZnwnBR #bioRxiv
L_I_B: Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice | bioRxiv https://t.co/vhJB3gHlpD
PrecursorCell: RT @biorxivpreprint: Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice https://t.co/2VL4ZnwnBR…
In_AnkitSingla: RT @biorxivpreprint: Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice https://t.co/2VL4ZnwnBR…
TheMainManManny: RT @biorxivpreprint: Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice https://t.co/2VL4ZnwnBR…
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Sample Sizes : None.
Authors: 18
Total Words: 15455
Unqiue Words: 3977

0.0 Mikeys
#9. The exon junction complex undergoes a compositional switch that alters mRNP structure and nonsense-mediated mRNA decay activity
Justin W Mabin, Lauren A Woodward, Robert Patton, Zhongxia Yi, Mengxuan Jia, Vicki Wysocki, Ralf Bundschuh, Guramrit Singh
The exon junction complex (EJC) deposited upstream of mRNA exon junctions shapes structure, composition and fate of spliced mRNA ribonucleoprotein particles (mRNPs). To achieve this, the EJC core nucleates assembly of a dynamic shell of peripheral proteins that function in diverse post-transcriptional processes. To illuminate consequences of EJC composition change, we purified EJCs from human cells via peripheral proteins RNPS1 and CASC3. We show that EJC originates as an SR-rich mega-dalton sized RNP that contains RNPS1 but lacks CASC3. After mRNP export to the cytoplasm and before translation, the EJC undergoes a remarkable compositional and structural remodeling into an SR-devoid monomeric complex that contains CASC3. Surprisingly, RNPS1 is important for nonsense-mediated mRNA decay (NMD) in general whereas CASC3 is needed for NMD of only select mRNAs. The promotion of switch to CASC3-EJC slows down NMD. Overall, the EJC compositional switch dramatically alters mRNP structure and specifies two distinct phases of EJC-dependent NMD.
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Authors: 8
Total Words: 13320
Unqiue Words: 3572

0.0 Mikeys
#10. Rapid Eye Movement sleep deprivation of rat generates ROS in the hepatocytes and make them more susceptible to oxidative stress
Atul Pandey, Santosh Kar
Background: Rapid Eye Movement sleep deprivation (REMSD) of rats causes inflammation of the liver, apoptotic cell death of the neurons and acute phase response to hepatocytes. Studies suggest that REMSD also facilitates the muscle and cardiac injury while same time causes depression like situation. Objective and methods: The aim of this research was to determine whether REMSD would create reactive oxygen species (ROS) and oxidative stress in hepatocytes of rats and how stress generated due to REMSD would make the hepatocytes susceptible to oxidative stress? We selectively deprived the rats for REMSD using established flower pot method. Results: We observed that with increase in the days of deprivation, the levels of ROS in the hepatocytes increased and it became normal when the rats were allowed to have recovery sleep for 5 days. Analysis of gene expression profile by real time PCR at different time of REMSD and the level of proteins by western blot analysis showed that there was increase in the expression of inducible nitric...
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atulpandeyjnu: Rapid Eye Movement sleep deprivation of rat generates ROS in the hepatocytes and make them more susceptible to oxidative stress https://t.co/Tgm3qQq84r
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Sample Sizes : [5]
Authors: 2
Total Words: 6425
Unqiue Words: 2065

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