scholarly journals Pathogenic mutations reveal a role of RECQ4 in mitochondrial RNA:DNA hybrid formation and resolution

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chou-Wei Chang ◽  
Xiaohua Xu ◽  
Min Li ◽  
Di Xin ◽  
Lin Ding ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Biochemical Analysis ◽  
Mitochondrial Localization ◽  
Protein Protein Interaction ◽  
Complex Process ◽  
Rna:Dna Hybrid ◽  
Rna:Dna Hybrids ◽  
Nucleic Acid Structures ◽  
Mitochondrial Membrane Protein

Abstract The synthesis of mitochondrial DNA (mtDNA) is a complex process that involves the formation and resolution of unusual nucleic acid structures, such as RNA:DNA hybrids. However, little is known about the enzymes that regulate these processes. RECQ4 is a DNA replication factor important for mtDNA maintenance, and here, we unveil a role of human RECQ4 in regulating the formation and resolution of mitochondrial RNA:DNA hybrids. Mitochondrial membrane protein p32 can block mtDNA synthesis by restricting RECQ4 mitochondrial localization via protein–protein interaction. We found that the interaction with p32 was disrupted not only by the previously reported cancer-associated RECQ4 mutation, del(A420-A463), but also by a clinical mutation of the adjacent residue, P466L. Surprisingly, although P466L mutant was present in the mitochondria at greater levels, unlike del(A420-A463) mutant, it failed to enhance mtDNA synthesis due to the accumulation of RNA:DNA hybrids throughout the mtDNA. Biochemical analysis revealed that P466L mutation enhanced RECQ4 annealing activity to generate RNA:DNA hybrids at the same time reduced its unwinding activity to resolve this structure. Hence, P466L mutation led to a reduced efficiency in completing mtDNA synthesis due to unresolved RNA:DNA hybrids across mtDNA.

scholarly journals Mitochondria-Associated Membranes (MAMs) are involved in Bax mitochondrial localization and cytochrome c release

2018 ◽  
Author(s):  
Alexandre Légiot ◽  
Claire Céré ◽  
Thibaud Dupoiron ◽  
Mohamed Kaabouni ◽  
Stéphen Manon
Keyword(s):  
Endoplasmic Reticulum ◽  
Cytochrome C ◽  
Mitochondrial Membrane ◽  
Human Protein ◽  
Outer Mitochondrial Membrane ◽  
Yeast Mutant ◽  
Mitochondrial Localization ◽  
Cytochrome C Release ◽  
Apoptotic Protein

AbstractThe distribution of the pro-apoptotic protein Bax in the outer mitochondrial membrane (OMM) is a central point of regulation of apoptosis. It is now widely recognized that parts of the endoplasmic reticulum (ER) are closely associated to the OMM, and are actively involved in different signalling processes. We adressed a possible role of these domains, called Mitochondria-Associated Membranes (MAMs) in Bax localization and fonction, by expressing the human protein in a yeast mutant deleted of MDM34, a ERMES component (ER-Mitochondria Encounter Structure). By affecting MAMs stability, the deletion of MDM34 altered Bax mitochondrial localization, and decreased its capacity to release cytochrome c. Furthermore, the deletion of MDM34 decreased the size of an uncompletely released, MAMs-associated pool of cytochrome c.

scholarly journals Dual role of Miro protein clusters in mitochondrial cristae organisation and ER-Mitochondria Contact Sites

2019 ◽  
Author(s):  
Souvik Modi ◽  
Guillermo López-Doménech ◽  
Elise F. Halff ◽  
Christian Covill-Cooke ◽  
Davor Ivankovic ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Super Resolution ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Localization ◽  
Mitochondrial Membranes ◽  
Mouse Embryonic Fibroblasts ◽  
Contact Site ◽  
Embryonic Fibroblasts ◽  
Regulated Trafficking

AbstractMitochondrial Rho (Miro) GTPases localize to the outer mitochondrial membrane and are essential machinery for the regulated trafficking of mitochondria to defined subcellular locations. However, their sub-mitochondrial localization and relationship with other critical mitochondrial complexes remains poorly understood. Here, using super-resolution fluorescence microscopy, we report that Miro proteins form nanometer-sized clusters along the mitochondrial outer membrane in association with the Mitochondrial Contact Site and Cristae Organizing System (MICOS). Using knockout mouse embryonic fibroblasts (MEF) we show that Miro1 and Miro2 are required for normal mitochondrial cristae architecture and endoplasmic reticulum-mitochondria contacts sites (ERMCS). Further, we show that Miro couples MICOS to TRAK motor protein adaptors to ensure the concerted transport of the two mitochondrial membranes and the correct distribution of cristae on the mitochondrial membrane. The Miro nanoscale organization, association with MICOS complex and regulation of ERMCS reveal new levels of control of the Miro GTPases on mitochondrial functionality.

scholarly journals qDRIP: Quantitative differential RNA:DNA hybrid immunoprecipitation sequencing

2019 ◽  
Author(s):  
Madzia P Crossley ◽  
Michael J Bocek ◽  
Stephan Hamperl ◽  
Tomek Swigut ◽  
Karlene A. Cimprich
Keyword(s):  
Absolute Count ◽  
Internal Standards ◽  
Physiological Processes ◽  
Quantitative Measurements ◽  
Genome Wide ◽  
Accurate Normalization ◽  
Rna:Dna Hybrid ◽  
Rna:Dna Hybrids ◽  
Nucleic Acid Structures ◽  
Generation Sequencing

AbstractR-loops are dynamic, co-transcriptional nucleic acid structures that facilitate physiological processes and cause DNA damage in certain contexts. Perturbations of transcription or R-loop resolution are expected to change their genomic distribution. Next-generation sequencing approaches to map RNA:DNA hybrids, a component of R-loops, have so far not allowed quantitative comparisons between such conditions. Here we describe quantitative differential RNA:DNA immunoprecipitation (qDRIP), a method combining synthetic RNA:DNA-hybrid internal standards with high-resolution, strand-specific sequencing. We show that qDRIP avoids biases inherent to read-count normalization by accurately profiling signal in regions unaffected by transcription inhibition in human cells, and by facilitating accurate differential peak calling between conditions. Finally, we use these quantitative comparisons to make the first estimates of the absolute count of RNA:DNA hybrids per cell and their half-lives genome-wide. Overall, qDRIP allows for accurate normalization in conditions where R-loops are perturbed and for quantitative measurements that provide previously unattainable biological insights.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

Social Cohesion, Breaks, and Transformations in Italy, 535–600

2018 ◽  
Author(s):  
Walter Pohl
Keyword(s):  
The Political ◽  
Late Antique ◽  
Religious Context ◽  
Ancient Society ◽  
Complex Process ◽  
Term Change ◽  
Two Generations ◽  
Classical Culture

When the Gothic War began in Italy in 535, the country still conserved many features of classical culture and late antique administration. Much of that was lost in the political upheavals of the following decades. Building on Chris Wickham’s work, this contribution sketches an integrated perspective of these changes, attempting to relate the contingency of events to the logic of long-term change, discussing political options in relation to military and economic means, and asking in what ways the erosion of consensus may be understood in a cultural and religious context. What was the role of military entrepreneurs of more or less barbarian or Roman extraction in the distribution or destruction of resources? How did Christianity contribute to the transformation of ancient society? The old model of barbarian invasions can contribute little to understanding this complex process. It is remarkable that for two generations, all political strategies in Italy ultimately failed.

scholarly journals Genome-wide identification of the GATA transcription factor family and their expression patterns under temperature and salt stress in Aspergillus oryzae

AMB Express ◽  
2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunmiao Jiang ◽  
Gongbo Lv ◽  
Jinxin Ge ◽  
Bin He ◽  
Zhe Zhang ◽  
...  
Keyword(s):  
Salt Stress ◽  
Expression Patterns ◽  
Interaction Network ◽  
Protein Protein Interaction ◽  
Genome Wide ◽  
Gata Transcription Factor ◽  
Starting Point ◽  
Evolutionary Features ◽  
First Time

AbstractGATA transcription factors (TFs) are involved in the regulation of growth processes and various environmental stresses. Although GATA TFs involved in abiotic stress in plants and some fungi have been analyzed, information regarding GATA TFs in Aspergillusoryzae is extremely poor. In this study, we identified and functionally characterized seven GATA proteins from A.oryzae 3.042 genome, including a novel AoSnf5 GATA TF with 20-residue between the Cys-X2-Cys motifs which was found in Aspergillus GATA TFs for the first time. Phylogenetic analysis indicated that these seven A. oryzae GATA TFs could be classified into six subgroups. Analysis of conserved motifs demonstrated that Aspergillus GATA TFs with similar motif compositions clustered in one subgroup, suggesting that they might possess similar genetic functions, further confirming the accuracy of the phylogenetic relationship. Furthermore, the expression patterns of seven A.oryzae GATA TFs under temperature and salt stresses indicated that A. oryzae GATA TFs were mainly responsive to high temperature and high salt stress. The protein–protein interaction network of A.oryzae GATA TFs revealed certain potentially interacting proteins. The comprehensive analysis of A. oryzae GATA TFs will be beneficial for understanding their biological function and evolutionary features and provide an important starting point to further understand the role of GATA TFs in the regulation of distinct environmental conditions in A.oryzae.

scholarly journals TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lisenn Lalier ◽  
Vincent Mignard ◽  
Marie-Pierre Joalland ◽  
Didier Lanoé ◽  
Pierre-François Cartron ◽  
...  
Keyword(s):  
Protein Import ◽  
Glioma Cells ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Localization ◽  
Antiapoptotic Protein ◽  
Mitochondrial Transfer ◽  
Small Domain ◽  
Induction Of Apoptosis ◽  
And Function

AbstractIn this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2–TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER–mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2–TOM20 interaction is thus an additional player in the control of apoptosis.

scholarly journals Consciousness, decision making, and volition: freedom beyond chance and necessity

2021 ◽  
Author(s):  
Hans Liljenström
Keyword(s):  
Decision Making ◽  
Free Will ◽  
Brain Activity ◽  
Brain Structures ◽  
Complex Process ◽  
Neural Information ◽  
Neural Information Processing ◽  
Stochastic Population Model ◽  
The Brain

AbstractWhat is the role of consciousness in volition and decision-making? Are our actions fully determined by brain activity preceding our decisions to act, or can consciousness instead affect the brain activity leading to action? This has been much debated in philosophy, but also in science since the famous experiments by Libet in the 1980s, where the current most common interpretation is that conscious free will is an illusion. It seems that the brain knows, up to several seconds in advance what “you” decide to do. These studies have, however, been criticized, and alternative interpretations of the experiments can be given, some of which are discussed in this paper. In an attempt to elucidate the processes involved in decision-making (DM), as an essential part of volition, we have developed a computational model of relevant brain structures and their neurodynamics. While DM is a complex process, we have particularly focused on the amygdala and orbitofrontal cortex (OFC) for its emotional, and the lateral prefrontal cortex (LPFC) for its cognitive aspects. In this paper, we present a stochastic population model representing the neural information processing of DM. Simulation results seem to confirm the notion that if decisions have to be made fast, emotional processes and aspects dominate, while rational processes are more time consuming and may result in a delayed decision. Finally, some limitations of current science and computational modeling will be discussed, hinting at a future development of science, where consciousness and free will may add to chance and necessity as explanation for what happens in the world.

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

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