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  1. Article ; Online: Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.

    Kramer, Nicholas J / Prakash, Gyan / Isaac, R Stefan / Choquet, Karine / Soto, Iliana / Petrova, Boryana / Merens, Hope E / Kanarek, Naama / Churchman, L Stirling

    Nature cell biology

    2023  Volume 25, Issue 11, Page(s) 1575–1589

    Abstract: Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression ... ...

    Abstract Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
    MeSH term(s) DNA, Mitochondrial/genetics ; DNA, Mitochondrial/metabolism ; RNA, Mitochondrial/metabolism ; Mitochondria/genetics ; Mitochondria/metabolism ; Gene Expression Regulation ; Oxidative Phosphorylation ; Nucleoside-Diphosphate Kinase/metabolism ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism
    Chemical Substances DNA, Mitochondrial ; RNA, Mitochondrial ; Nucleoside-Diphosphate Kinase (EC 2.7.4.6) ; Mitochondrial Proteins
    Language English
    Publishing date 2023-09-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-023-01244-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5169: Show issues Location:
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    Zs.MG 12: Show issues

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  2. Article: Genome-wide screens for mitonuclear co-regulators uncover links between compartmentalized metabolism and mitochondrial gene expression.

    Kramer, Nicholas J / Prakash, Gyan / Choquet, Karine / Soto, Iliana / Petrova, Boryana / Merens, Hope E / Kanarek, Naama / Churchman, L Stirling

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells, in which gene expression must be ... ...

    Abstract Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells, in which gene expression must be coordinated across organelles using distinct pools of ribosomes. How cells produce and maintain the accurate subunit stoichiometries for these OXPHOS complexes remains largely unknown. To identify genes involved in dual-origin protein complex synthesis, we performed FACS-based genome-wide screens analyzing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of cytochrome
    Language English
    Publishing date 2023-02-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.11.528118
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Revealing nascent RNA processing dynamics with nano-COP.

    Drexler, Heather L / Choquet, Karine / Merens, Hope E / Tang, Paul S / Simpson, Jared T / Churchman, L Stirling

    Nature protocols

    2021  Volume 16, Issue 3, Page(s) 1343–1375

    Abstract: During maturation, eukaryotic precursor RNAs undergo processing events including intron splicing, 3'-end cleavage, and polyadenylation. Here we describe nanopore analysis of co-transcriptional processing (nano-COP), a method for probing the timing and ... ...

    Abstract During maturation, eukaryotic precursor RNAs undergo processing events including intron splicing, 3'-end cleavage, and polyadenylation. Here we describe nanopore analysis of co-transcriptional processing (nano-COP), a method for probing the timing and patterns of RNA processing. An extension of native elongating transcript sequencing, which quantifies transcription genome-wide through short-read sequencing of nascent RNA 3' ends, nano-COP uses long-read nascent RNA sequencing to observe global patterns of RNA processing. First, nascent RNA is stringently purified through a combination of 4-thiouridine metabolic labeling and cellular fractionation. In contrast to cDNA or short-read-based approaches relying on reverse transcription or amplification, the sample is sequenced directly through nanopores to reveal the native context of nascent RNA. nano-COP identifies both active transcription sites and splice isoforms of single RNA molecules during synthesis, providing insight into patterns of intron removal and the physical coupling between transcription and splicing. The nano-COP protocol yields data within 3 d.
    MeSH term(s) Animals ; Exons/genetics ; Humans ; Introns/genetics ; Protein Modification, Translational/genetics ; Protein Modification, Translational/physiology ; RNA/genetics ; RNA Polymerase II/metabolism ; RNA Precursors/analysis ; RNA Precursors/genetics ; RNA Precursors/metabolism ; RNA Processing, Post-Transcriptional/genetics ; RNA Processing, Post-Transcriptional/physiology ; RNA Splicing/genetics ; RNA, Messenger/genetics ; Sequence Analysis, RNA/methods ; Transcription, Genetic/genetics
    Chemical Substances RNA Precursors ; RNA, Messenger ; RNA (63231-63-0) ; RNA Polymerase II (EC 2.7.7.-)
    Language English
    Publishing date 2021-01-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2244966-8
    ISSN 1750-2799 ; 1754-2189
    ISSN (online) 1750-2799
    ISSN 1754-2189
    DOI 10.1038/s41596-020-00469-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: RNA Polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.

    Martell, Danya J / Merens, Hope E / Fiorini, Claudia / Caulier, Alexis / Ulirsch, Jacob C / Ietswaart, Robert / Choquet, Karine / Graziadei, Giovanna / Brancaleoni, Valentina / Cappellini, Maria Domenica / Scott, Caroline / Roberts, Nigel / Proven, Melanie / Roy, Noémi Ba / Babbs, Christian / Higgs, Douglas R / Sankaran, Vijay G / Churchman, L Stirling

    medRxiv : the preprint server for health sciences

    2023  

    Abstract: The controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are ... ...

    Abstract The controlled release of promoter-proximal paused RNA polymerase II (Pol II) into productive elongation is a major step in gene regulation. However, functional analysis of Pol II pausing is difficult because factors that regulate pause release are almost all essential. In this study, we identified heterozygous loss-of-function mutations in
    Language English
    Publishing date 2023-03-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.03.03.23286760
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation.

    Martell, Danya J / Merens, Hope E / Caulier, Alexis / Fiorini, Claudia / Ulirsch, Jacob C / Ietswaart, Robert / Choquet, Karine / Graziadei, Giovanna / Brancaleoni, Valentina / Cappellini, Maria Domenica / Scott, Caroline / Roberts, Nigel / Proven, Melanie / Roy, Noémi B A / Babbs, Christian / Higgs, Douglas R / Sankaran, Vijay G / Churchman, L Stirling

    Developmental cell

    2023  Volume 58, Issue 20, Page(s) 2112–2127.e4

    Abstract: Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified ... ...

    Abstract Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified heterozygous loss-of-function mutations in SUPT5H, which encodes SPT5, in individuals with β-thalassemia. During erythropoiesis in healthy human cells, cell cycle genes were highly paused as cells transition from progenitors to precursors. When the pathogenic mutations were recapitulated by SUPT5H editing, RNA Pol II pause release was globally disrupted, and as cells began transitioning from progenitors to precursors, differentiation was delayed, accompanied by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, identifying a role for RNA Pol II pausing in temporally coordinating the cell cycle and erythroid differentiation.
    MeSH term(s) Humans ; RNA Polymerase II/genetics ; RNA Polymerase II/metabolism ; Gene Expression Regulation ; Cell Differentiation ; Cell Cycle ; Transcription, Genetic ; Nuclear Proteins/metabolism ; Transcriptional Elongation Factors/genetics
    Chemical Substances RNA Polymerase II (EC 2.7.7.-) ; SUPT5H protein, human ; Nuclear Proteins ; Transcriptional Elongation Factors
    Language English
    Publishing date 2023-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2023.07.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5742: Show issues Location:
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  6. Article ; Online: Polyphosphate Initiates Tau Aggregation through Intra- and Intermolecular Scaffolding.

    Wickramasinghe, Sanjula P / Lempart, Justine / Merens, Hope E / Murphy, Jacob / Huettemann, Philipp / Jakob, Ursula / Rhoades, Elizabeth

    Biophysical journal

    2019  Volume 117, Issue 4, Page(s) 717–728

    Abstract: The aggregation and deposition of tau is a hallmark of a class of neurodegenerative diseases called tauopathies. Despite intensive study, cellular and molecular factors that trigger tau aggregation are not well understood. Here, we provide evidence for ... ...

    Abstract The aggregation and deposition of tau is a hallmark of a class of neurodegenerative diseases called tauopathies. Despite intensive study, cellular and molecular factors that trigger tau aggregation are not well understood. Here, we provide evidence for two mechanisms relevant to the initiation of tau aggregation in the presence of cytoplasmic polyphosphates (polyP): changes in the conformational ensemble of monomer tau and noncovalent cross-linking of multiple tau monomers. We identified conformational changes throughout full-length tau, most notably diminishment of long-range interactions between the termini coupled with compaction of the microtubule binding and proline- rich regions. We found that while the proline-rich and microtubule binding regions both contain polyP binding sites, the proline-rich region is a requisite for compaction of the microtubule binding region upon binding. Additionally, both the magnitude of the conformational change and the aggregation of tau are dependent on the chain length of the polyP polymer. Longer polyP chains are more effective at intermolecular, noncovalent cross-linking of tau. These observations provide an understanding of the initial steps of tau aggregation through interaction with a physiologically relevant aggregation inducer.
    MeSH term(s) Binding Sites ; Humans ; Microtubules/metabolism ; Mutation ; Polyphosphates/chemistry ; Polyphosphates/metabolism ; Proline-Rich Protein Domains ; Protein Aggregates ; Protein Binding ; Single Molecule Imaging ; tau Proteins/chemistry ; tau Proteins/genetics ; tau Proteins/metabolism
    Chemical Substances Polyphosphates ; Protein Aggregates ; tau Proteins
    Language English
    Publishing date 2019-07-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2019.07.028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 235: Show issues Location:
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    Zs.MO 2: Show issues

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