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  • 1
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    Staufen1 promotes HCV replication by inhibiting protein kinase R and transporting viral RNA to the site of translation and replication in the cells (2016)
    Oxford University Press
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    Publication Date: 2016-06-21
    Description: Persistent hepatitis C virus (HCV) infection leads to chronic hepatitis C (CHC), which often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The molecular mechanisms that establish CHC and cause its subsequent development into LC and HCC are poorly understood. We have identified a cytoplasmic double-stranded RNA binding protein, Stau1, which is crucial for HCV replication. In this study, Stau1 specifically interacted with the variable-stem-loop region in the 3' NTR and domain IIId of the HCV-IRES in the 5' NTR, and promoted HCV replication and translation. Stau1 coimmunoprecipitates HCV NS5B and a cell factor, protein kinase R (PKR), which is critical for interferon-induced cellular antiviral and antiproliferative responses. Like Stau1, PKR displayed binding specificity to domain IIId of HCV-IRES. Stau1 binds to PKR and strongly inhibits PKR-autophosphorylation. We demonstrated that the transport of HCV RNA on the polysomes is Stau1-dependent, being mainly localized in the monosome fractions when Stau1 is downregulated and exclusively localized in the polysomes when Stau1 is overexpressed. Our findings suggest that HCV may appropriate Stau1 to its advantage to prevent PKR-mediated inhibition of eIF2α, which is required for the synthesis of HCV proteins for translocation of viral RNA genome to the polysomes for efficient translation and replication.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Novel mechanism of gene regulation: the protein Rv1222 of Mycobacterium tuberculosis inhibits transcription by anchoring the RNA polymerase onto DNA (2015)
    Oxford University Press
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    Publication Date: 2015-07-12
    Description: We propose a novel mechanism of gene regulation in Mycobacterium tuberculosis where the protein Rv1222 inhibits transcription by anchoring RNA polymerase (RNAP) onto DNA. In contrast to our existing knowledge that transcriptional repressors function either by binding to DNA at specific sequences or by binding to RNAP, we show that Rv1222-mediated transcription inhibition requires simultaneous binding of the protein to both RNAP and DNA. We demonstrate that the positively charged C-terminus tail of Rv1222 is responsible for anchoring RNAP on DNA, hence the protein slows down the movement of RNAP along the DNA during transcription elongation. The interaction between Rv1222 and DNA is electrostatic, thus the protein could inhibit transcription from any gene. As Rv1222 slows down the RNA synthesis, upon expression of the protein in Mycobacterium smegmatis or Escherichia coli , the growth rate of the bacteria is severely impaired. The protein does not possess any significant affinity for DNA polymerase, thus, is unable to inhibit DNA synthesis. The proposed mechanism by which Rv1222 inhibits transcription reveals a new repertoire of prokaryotic gene regulation.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples (2016)
    Oxford University Press
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    Publication Date: 2016-02-20
    Description: Somatic mosaicism refers to the existence of somatic mutations in a fraction of somatic cells in a single biological sample. Its importance has mainly been discussed in theory although experimental work has started to emerge linking somatic mosaicism to disease diagnosis. Through novel statistical modeling of paired-end DNA-sequencing data using blood-derived DNA from healthy donors as well as DNA from tumor samples, we present an ultra-fast computational pipeline, LocHap that searches for multiple single nucleotide variants (SNVs) that are scaffolded by the same reads. We refer to scaffolded SNVs as local haplotypes (LH). When an LH exhibits more than two genotypes, we call it a local haplotype variant (LHV). The presence of LHVs is considered evidence of somatic mosaicism because a genetically homogeneous cell population will not harbor LHVs. Applying LocHap to whole-genome and whole-exome sequence data in DNA from normal blood and tumor samples, we find wide-spread LHVs across the genome. Importantly, we find more LHVs in tumor samples than in normal samples, and more in older adults than in younger ones. We confirm the existence of LHVs and somatic mosaicism by validation studies in normal blood samples. LocHap is publicly available at http://www.compgenome.org/lochap .
    Keywords: Polymorphism/mutation detection
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Interactions of the TnaC nascent peptide with rRNA in the exit tunnel enable the ribosome to respond to free tryptophan (2014)
    Oxford University Press
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    Publication Date: 2014-01-28
    Description: A transcriptional attenuation mechanism regulates expression of the bacterial tnaCAB operon. This mechanism requires ribosomal arrest induced by the regulatory nascent TnaC peptide in response to free L-tryptophan (L-Trp). In this study we demonstrate, using genetic and biochemical analyses, that in Escherichia coli , TnaC residue I19 and 23S rRNA nucleotide A2058 are essential for the ribosome’s ability to sense free L-Trp. We show that the mutational change A2058U in 23S rRNA reduces the concentration dependence of L-Trp-mediated tna operon induction, whereas the TnaC I19L change suppresses this phenotype, restoring the sensitivity of the translating A2058U mutant ribosome to free L-Trp. These findings suggest that interactions between TnaC residue I19 and 23S rRNA nucleotide A2058 contribute to the creation of a regulatory L-Trp binding site within the translating ribosome.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage (2014)
    Oxford University Press
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    Publication Date: 2014-04-15
    Description: Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3'-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1–PARP1 complexes, in turn recruit X-ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Chromosome positioning from activity-based segregation (2014)
    Oxford University Press
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    Publication Date: 2014-04-15
    Description: Chromosomes within eukaryotic cell nuclei at interphase are not positioned at random, since gene-rich chromosomes are predominantly found towards the interior of the cell nucleus across a number of cell types. The physical mechanisms that could drive and maintain the spatial segregation of chromosomes based on gene density are unknown. Here, we identify a mechanism for such segregation, showing that the territorial organization of chromosomes, another central feature of nuclear organization, emerges naturally from our model. Our computer simulations indicate that gene density-dependent radial segregation of chromosomes arises as a robust consequence of differences in non-equilibrium activity across chromosomes. Arguing that such differences originate in the inhomogeneous distribution of ATP-dependent chromatin remodeling and transcription machinery on each chromosome, we show that a variety of non-random positional distributions emerge through the interplay of such activity, nuclear shape and specific interactions of chromosomes with the nuclear envelope. Results from our model are in reasonable agreement with experimental data and we make a number of predictions that can be tested in experiments.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Genome-wide analysis reveals distinct patterns of epigenetic features in long non-coding RNA loci (2012)
    Oxford University Press
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    Publication Date: 2012-11-04
    Description: A major fraction of the transcriptome of higher organisms comprised an extensive repertoire of long non-coding RNA (lncRNA) which express in a cell type and development stage-specific manner. While lncRNAs are a proven component of epigenetic gene expression modulation, epigenetic regulation of lncRNA itself remains poorly understood. Here we have analysed pan-genomic DNA methylation and histone modification marks (H3K4me3, H3K9me3, H3K27me3 and H3K36me3) associated with transcription start site (TSS) of lncRNA in four different cell types and three different tissue types representing various cellular stages. We observe that histone marks associated with active transcription H3K4me3 and H3K36me3 along with the repressive histone mark H3K27me3 have similar distribution pattern around TSS irrespective of cell types. Also, the density of these marks correlates well with expression of protein-coding and lncRNA genes. In contrast, the lncRNA genes harbour higher methylation density around TSS than protein-coding genes regardless of their expression status. Furthermore, we found that DNA methylation along with the other repressive histone mark H3K9me3 does not seem to play a role in lncRNA expression. Thus, our observation suggests that epigenetic regulation of lncRNA shares common features with mRNA except the role of DNA methylation which is markedly dissimilar.
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    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Poly(ADP-ribose) polymers regulate DNA topoisomerase I (Top1) nuclear dynamics and camptothecin sensitivity in living cells (2016)
    Oxford University Press
    Details
    Publication Date: 2016-10-08
    Description: Topoisomerase 1 (Top1) is essential for removing the DNA supercoiling generated during replication and transcription. Anticancer drugs like camptothecin (CPT) and its clinical derivatives exert their cytotoxicity by reversibly trapping Top1 in covalent complexes on the DNA (Top1cc). Poly(ADP-ribose) polymerase (PARP) catalyses the addition of ADP-ribose polymers (PAR) onto itself and Top1. PARP inhibitors enhance the cytotoxicity of CPT in the clinical trials. However, the molecular mechanism by which PARylation regulates Top1 nuclear dynamics is not fully understood. Using live-cell imaging of enhanced green fluorescence tagged-human Top1, we show that PARP inhibitors (Veliparib, ABT-888) delocalize Top1 from the nucleolus to the nucleoplasm, which is independent of Top1–PARP1 interaction. Using fluorescence recovery after photobleaching and subsequent fitting of the data employing kinetic modelling we demonstrate that ABT-888 markedly increase CPT-induced bound/immobile fraction of Top1 (Top1cc) across the nuclear genome, suggesting Top1-PARylation counteracts CPT-induced stabilization of Top1cc. We further show Trp205 and Asn722 of Top1 are critical for subnuclear dynamics. Top1 mutant (N722S) was restricted to the nucleolus in the presence of CPT due to its deficiency in the accumulation of CPT-induced Top1-PARylation and Top1cc formation. This work identifies ADP-ribose polymers as key determinant for regulating Top1 subnuclear dynamics.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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