Journal of Molecular Biology

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  • Large Tilts in Transmembrane Helices Can Be Induced during Tertiary Structure Formation
    [Jun 2014]

    Publication date: 26 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 13

    Author(s): Minttu Virkki , Carolina Boekel , Kristoffer Illergård , Christoph Peters , Nanjiang Shu , Konstantinos D. Tsirigos , Arne Elofsson , Gunnar von Heijne , IngMarie Nilsson

    While early structural models of helix-bundle integral membrane proteins posited that the transmembrane α-helices [transmembrane helices (TMHs)] were orientated more or less perpendicular to the membrane plane, there is now ample evidence from high-resolution structures that many TMHs have significant tilt angles relative to the membrane. Here, we address the question whether the tilt is an intrinsic property of the TMH in question or if it is imparted on the TMH during folding of the protein. Using a glycosylation mapping technique, we show that four highly tilted helices found in multi-spanning membrane proteins all have much shorter membrane-embedded segments when inserted by themselves into the membrane than seen in the high-resolution structures. This suggests that tilting can be induced by tertiary packing interactions within the protein, subsequent to the initial membrane-insertion step.
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    Categories: Journal Articles
  • Editorial Board
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12









    Categories: Journal Articles
  • Contents List
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12









    Categories: Journal Articles
  • Beyond DnaA: The Role of DNA Topology and DNA Methylation in Bacterial Replication Initiation
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Rafał Donczew , Jolanta Zakrzewska-Czerwińska , Anna Zawilak-Pawlik

    The replication of chromosomal DNA is a fundamental event in the life cycle of every cell. The first step of replication, initiation, is controlled by multiple factors to ensure only one round of replication per cell cycle. The process of initiation has been described most thoroughly for bacteria, especially Escherichia coli, and involves many regulatory proteins that vary considerably between different species. These proteins control the activity of the two key players of initiation in bacteria: the initiator protein DnaA and the origin of chromosome replication (oriC). Factors involved in the control of the availability, activity, or oligomerization of DnaA during initiation are generally regarded as the most important and thus have been thoroughly characterized. Other aspects of the initiation process, such as origin accessibility and susceptibility to unwinding, have been less explored. However, recent findings indicate that these factors have a significant role. This review focuses on DNA topology, conformation, and methylation as important factors that regulate the initiation process in bacteria. We present a comprehensive summary of the factors involved in the modulation of DNA topology, both locally at oriC and more globally at the level of the entire chromosome. We show clearly that the conformation of oriC dynamically changes, and control of this conformation constitutes another, important factor in the regulation of bacterial replication initiation. Furthermore, the process of initiation appears to be associated with the dynamics of the entire chromosome and this association is an important but largely unexplored phenomenon.
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  • A Non-Active-Site SET Domain Surface Crucial for the Interaction of MLL1 and the RbBP5/Ash2L Heterodimer within MLL Family Core Complexes
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Stephen A. Shinsky , Michael Hu , Valarie E. Vought , Sarah B. Ng , Michael J. Bamshad , Jay Shendure , Michael S. Cosgrove

    The mixed lineage leukemia-1 (MLL1) enzyme is a histone H3 lysine 4 (H3K4) monomethyltransferase and has served as a paradigm for understanding the mechanism of action of the human SET1 family of enzymes that include MLL1–MLL4 and SETd1a,b. Dimethylation of H3K4 requires a sub-complex including WRAD (WDR5, RbBP5, Ash2L, and DPY-30), which binds to each SET1 family member forming a minimal core complex that is required for multiple lysine methylation. We recently demonstrated that WRAD is a novel histone methyltransferase that preferentially catalyzes H3K4 dimethylation in a manner that is dependent on an unknown non-active-site surface from the MLL1 SET domain. Recent genome sequencing studies have identified a number of human disease-associated missense mutations that localize to the SET domains of several MLL family members. In this investigation, we mapped many of these mutations onto the three-dimensional structure of the SET domain and noticed that a subset of MLL2 (KMT2D, ALR, MLL4)-associated Kabuki syndrome missense mutations map to a common solvent-exposed surface that is not expected to alter enzymatic activity. We introduced these mutations into the MLL1 SET domain and observed that all are defective for H3K4 dimethylation by the MLL1 core complex, which is associated with a loss of the ability of MLL1 to interact with WRAD or with the RbBP5/Ash2L heterodimer. Our results suggest that amino acids from this surface, which we term the Kabuki interaction surface or KIS, are required for formation of a second active site within SET1 family core complexes.
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  • Folding Pathways of the Tetrahymena Ribozyme
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): David Mitchell III , Rick Russell

    Like many structured RNAs, the Tetrahymena group I intron ribozyme folds through multiple pathways and intermediates. Under standard conditions in vitro, a small fraction reaches the native state (N) with k obs ≈0.6min−1, while the remainder forms a long-lived misfolded conformation (M) thought to differ in topology. These alternative outcomes reflect a pathway that branches late in folding, after disruption of a trapped intermediate (Itrap). Here we use catalytic activity to probe the folding transitions from Itrap to the native and misfolded states. We show that mutations predicted to weaken the core helix P3 do not increase the rate of folding from Itrap but they increase the fraction that reaches the native state rather than forming the misfolded state. Thus, P3 is disrupted during folding to the native state but not to the misfolded state, and P3 disruption occurs after the rate-limiting step. Interestingly, P3-strengthening mutants also increase native folding. Additional experiments show that these mutants are rapidly committed to folding to the native state, although they reach the native state with approximately the same rate constant as the wild-type ribozyme (~1min−1). Thus, the P3-strengthening mutants populate a distinct pathway that includes at least one intermediate but avoids the M state, most likely because P3 and the correct topology are formed early. Our results highlight multiple pathways in RNA folding and illustrate how kinetic competitions between rapid events can have long-lasting effects because the “choice” is enforced by energy barriers that grow larger as folding progresses.
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  • The Crystal Structure of the Anti-σ Factor CnrY in Complex with the σ Factor CnrH Shows a New Structural Class of Anti-σ Factors Targeting Extracytoplasmic Function σ Factors
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Antoine P. Maillard , Eric Girard , Widade Ziani , Isabelle Petit-Härtlein , Richard Kahn , Jacques Covès

    Gene expression in bacteria is regulated at the level of transcription initiation, a process driven by σ factors. The regulation of σ factor activity proceeds from the regulation of their cytoplasmic availability, which relies on specific inhibitory proteins called anti-σ factors. With anti-σ factors regulating their availability according to diverse cues, extracytoplasmic function σ factors (σECF) form a major signal transduction system in bacteria. Here, structure:function relationships have been characterized in an emerging class of minimal-size transmembrane anti-σ factors, using CnrY from Cupriavidus metallidurans CH34 as a model. This study reports the 1.75-Å-resolution structure of CnrY cytosolic domain in complex with CnrH, its cognate σECF, and identifies a small hydrophobic knob in CnrY as the major determinant of this interaction in vivo. Unsuspected structural similarity with the molecular switch regulating the general stress response in α-proteobacteria unravels a new class of anti-σ factors targeting σECF. Members of this class carry out their function via a 30-residue stretch that displays helical propensity but no canonical structure on its own.
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  • Alanine Scanning Mutagenesis Identifies an Asparagine–Arginine–Lysine Triad Essential to Assembly of the Shell of the Pdu Microcompartment
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Sharmistha Sinha , Shouqiang Cheng , Yea Won Sung , Dan E. McNamara , Michael R. Sawaya , Todd O. Yeates , Thomas A. Bobik

    Bacterial microcompartments (MCPs) are the simplest organelles known. They function to enhance metabolic pathways by confining several related enzymes inside an all-protein envelope called the shell. In this study, we investigated the factors that govern MCP assembly by performing scanning mutagenesis on the surface residues of PduA, a major shell protein of the MCP used for 1,2-propanediol degradation. Biochemical, genetic, and structural analysis of 20 mutants allowed us to determine that PduA K26, N29, and R79 are crucial residues that stabilize the shell of the 1,2-propanediol MCP. In addition, we identify two PduA mutants (K37A and K55A) that impair MCP function most likely by altering the permeability of its protein shell. These are the first studies to examine the phenotypic effects of shell protein structural mutations in an MCP system. The findings reported here may be applicable to engineering protein containers with improved stability for biotechnology applications.
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  • Co-Crystallization with Conformation-Specific Designed Ankyrin Repeat Proteins Explains the Conformational Flexibility of BCL-W
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Johannes Schilling , Jendrik Schöppe , Evelyn Sauer , Andreas Plückthun

    BCL-W is a member of the BCL-2 family of anti-apoptotic proteins. A key event in the regulation of apoptosis is the heterodimerization between anti-apoptotic and pro-apoptotic family members, which involves a conserved surface-exposed groove on the anti-apoptotic proteins. Crystal structures of the ligand binding-competent conformation exist for all anti-apoptotic family members, with the exception of BCL-W, due to the flexibility of the BCL-W groove region. Existing structures had suggested major deviations of the BCL-W groove region from the otherwise structurally highly related remaining anti-apoptotic family members. To capture its ligand binding-competent conformation by counteracting the conformational flexibility of the BCL-W groove, we had selected high-affinity groove-binding designed ankyrin repeat proteins (DARPins) using ribosome display. We now determined two high-resolution crystal structures of human BCL-W in complex with different DARPins at resolutions 1.5 and 1.85Å, in which the structure of BCL-W is virtually identical, and BCL-W adopts a conformation extremely similar to the ligand-free conformation of its closest relative BCL-XL in both structures. However, distinct differences to all previous BCL-W structures are evident, notably in the ligand-binding region. We provide the first structural explanation for the conformational flexibility of the BCL-W groove region in comparison to other BCL-2 family members. Due to the importance of the anti-apoptotic BCL-2 family as drug targets, the presented crystal structure of ligand binding-competent BCL-W may serve as a valuable basis for structure-based drug design in the future and provides a missing piece for the structural characterization of this protein family.
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  • The Nucleolar PICT-1/GLTSCR2 Protein Forms Homo-Oligomers
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Tatyana Borodianskiy-Shteinberg , Inna Kalt , Sarit Kipper , Nofar Nachum , Shiri Katz , Maor H. Pauker , Mira Barda-Saad , Doron Gerber , Ronit Sarid

    The human “protein interacting with carboxyl terminus 1” (PICT-1), also designated as the “glioma tumor suppressor candidate region 2 gene product”, GLTSCR2, is a nucleolar protein whose activity is, as yet, unknown. Contradictory results regarding the role of PICT-1 in cancer have been reported, and PICT-1 has been suggested to function either as a tumor suppressor protein or as an oncogene. In this study, we demonstrate self-association of PICT-1. Through yeast two-hybrid assay, we identified PICT-1 as its own interaction partner. We confirmed the interaction of PICT-1 with itself by direct yeast two-hybrid assay and also showed self-association of PICT-1 in mammalian cells by co-immunoprecipitation and fluorescence resonance energy transfer assays. Furthermore, we confirmed direct self-association of PICT-1 by using in vitro microfluidic affinity binding assays. The later assay also identified the carboxy-terminal domain as mediating self-interaction of PICT-1. Glutaraldehyde cross-linking and gel-filtration assays suggest that PICT-1 forms dimers, though it may form higher-order complexes as well. Our findings add another layer of complexity in understanding the different functions of PICT-1 and may help provide insights regarding the activities of this protein.
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    Categories: Journal Articles
  • A Mutation in the Catalytic Loop of Hsp90 Specifically Impairs ATPase Stimulation by Aha1p, But Not Hch1p
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Natalie K. Horvat , Heather Armstrong , Brian L. Lee , Rebecca Mercier , Annemarie Wolmarans , Jacob Knowles , Leo Spyracopoulos , Paul LaPointe

    Heat shock protein 90 (Hsp90) is a molecular chaperone that plays a central role in maintaining cellular homeostasis by facilitating activation of a large number of client proteins. ATP-dependent client activation by Hsp90 is tightly regulated by a host of co-chaperone proteins that control progression through the activation cycle. ATPase stimulation of Hsp90 by Aha1p requires a conserved RKxK motif that interacts with the catalytic loop of Hsp90. In this study, we explore the role of this RKxK motif in the biological and biochemical properties of Hch1p. We found that this motif is required for Hch1p-mediated ATPase stimulation in vitro, but mutations that block stimulation do not impair the action of Hch1p in vivo. This suggests that the biological function of Hch1p is not directly linked to ATPase stimulation. Moreover, a mutation in the catalytic loop of Hsp90 specifically impairs ATPase stimulation by Aha1p but not by Hch1p. Our work here suggests that both Hch1p and Aha1p regulate Hsp90 function through interaction with the catalytic loop but do so in different ways.
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    Categories: Journal Articles
  • Elucidating the Mechanism of Substrate Recognition by the Bacterial Hsp90 Molecular Chaperone
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Timothy O. Street , Xiaohui Zeng , Riccardo Pellarin , Massimiliano Bonomi , Andrej Sali , Mark J.S. Kelly , Feixia Chu , David A. Agard

    Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates (“clients”). Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging. Using a partially folded protein as a model system, we find that the bacterial Hsp90 adapts its conformation to the substrate, forming a binding site that spans the middle and C-terminal domains of the chaperone. Cross-linking and NMR measurements indicate that Hsp90 binds to a large partially folded region of the substrate and significantly alters both its local and long-range structure. These findings implicate Hsp90's conformational dynamics in its ability to bind and remodel partially folded proteins. Moreover, native-state hydrogen exchange indicates that Hsp90 can also interact with partially folded states only transiently populated from within a thermodynamically stable, native-state ensemble. These results suggest a general mechanism by which Hsp90 can recognize and remodel native proteins by binding and remodeling partially folded states that are transiently sampled from within the native ensemble.
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  • A Genome-Wide Sequence–Structure Analysis Suggests Aggregation Gatekeepers Constitute an Evolutionary Constrained Functional Class
    [Jun 2014]

    Publication date: 12 June 2014
    Source:Journal of Molecular Biology, Volume 426, Issue 12

    Author(s): Greet De Baets , Joost Van Durme , Frederic Rousseau , Joost Schymkowitz

    Protein aggregation is geared by aggregation-prone regions that self-associate by β-strand interactions. Charged residues and prolines are enriched at the flanks of aggregation-prone regions resulting in decreased aggregation. It is still unclear what drives the overrepresentation of these “aggregation gatekeepers”, that is, whether their presence results from structural constraints determining protein stability or whether they constitute a bona fide functional class selectively maintained to control protein aggregation. As functional residues are typically conserved regardless of their cost to protein stability, we compared sequence conservation and thermodynamic cost of these residues in 2659 protein families in Escherichia coli. Across protein families, we find gatekeepers to be under strong selective conservation while at the same time representing a significant thermodynamic cost to protein structure. This finding supports the notion that aggregation gatekeepers are not structurally determined but evolutionary selected to control protein aggregation.
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  • The positive inside rule is stronger when followed by a transmembrane helix
    [Jun 2014]

    Publication date: Available online 10 June 2014
    Source:Journal of Molecular Biology

    Author(s): Minttu T. Virkki , Christoph Peters , Daniel Nilsson , Therese Sörensen , Susana Cristobal , Björn Wallner , Arne Elofsson

    The translocon recognizes transmembrane helices with sufficient level of hydrophobicity and inserts them into the membrane. However, sometimes less hydrophobic helices are also recognized. Positive inside rule, orientational preferences of and specific interactions with neighboring helices have been shown to aid in the recognition of these helices, at least in artificial systems. To better understand how the translocon inserts marginally hydrophobic helices, we studied three naturally occurring marginally hydrophobic helices, which were previously shown to require the subsequent helix for efficient translocon recognition. We find no evidence for specific interactions when we scan all residues in the subsequent helices. Instead, we identify arginines located at the N-terminal part of the subsequent helices that are crucial for the recognition of the marginally hydrophobic transmembrane helices, indicating that the positive inside rule is important. However, in two of the constructs these arginines do not aid in the recognition without the rest of the subsequent helix, i.e. the positive inside rule alone is not sufficient. Instead, the improved recognition of marginally hydrophobic helices can here be explained as follows; the positive inside rule provides an orientational preference of the subsequent helix, which in turn allows the marginally hydrophobic helix to be inserted, i.e. the effect of the positive inside rule is stronger if positively charged residues are followed by a transmembrane helix. Such a mechanism can obviously not aid C-terminal helices and consequently we find that the terminal helices in multi-spanning membrane proteins are more hydrophobic than internal helices.
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  • Sus1p facilitates pre-initiation complex formation at the SAGA-regulated genes independently of histone H2B de-ubiquitylation
    [Jun 2014]

    Publication date: Available online 6 June 2014
    Source:Journal of Molecular Biology

    Author(s): Geetha Durairaj , Rwik Sen , Bhawana Uprety , Abhijit Shukla , Sukesh R. Bhaumik

    Sus1p is a common component of transcriptional co-activator, SAGA (Spt-Ada-Gcn5-Acetyltransferase), and mRNA export complex, TREX-2 (Transcription-export 2), and is involved in promoting transcription as well as mRNA export. However, it is not clearly understood how Sus1p promotes transcription. Here, we show that Sus1p is predominantly recruited to the upstream activating sequence of a SAGA-dependent gene, GAL1, under transcriptionally active conditions as a component of SAGA to promote the formation of pre-initiation complex (PIC) at the core promoter, and consequently, transcriptional initiation. Likewise, Sus1p promotes the PIC formation at other SAGA-dependent genes, and hence transcriptional initiation. Such function of Sus1p in promoting PIC formation and transcriptional initiation is not mediated via its role in regulation of SAGA’s histone H2B de-ubiquitylation activity. However, Sus1p’s function in regulation of histone H2B ubiquitylation is associated with transcriptional elongation, DNA repair and replication. Collectively, our results support that Sus1p promotes PIC formation (and hence transcriptional initiation) at the SAGA-regulated genes independently of histone H2B de-ubiquitylation, and further controls transcriptional elongation, DNA repair and replication via orchestration of histone H2B ubiquitylation, thus providing distinct functional insights of Sus1p in regulation of DNA transacting processes.
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    Categories: Journal Articles
  • The Yin and Yang of Bacterial Resilience in the Human Gut Microbiota
    [Jun 2014]

    Publication date: Available online 6 June 2014
    Source:Journal of Molecular Biology

    Author(s): Molly K. Gibson , Mitchell W. Pesesky , Gautam Dantas

    The human gut is home to trillions of microbes that form a symbiotic relationship with the human host. During health, the intestinal microbiota provides many benefits to the host and is generally resistant to colonization by new species; however, disruption of this complex community can lead to pathogen invasion, inflammation, and disease. Restoration and maintenance of a healthy gut microbiota composition requires effective therapies to reduce and prevent colonization of harmful bacteria (pathogens) while simultaneously promoting growth of beneficial bacteria (probiotics). Here we review the mechanisms by which the host modulates the gut community composition during health and disease, and discuss prospects for antibiotic and probiotic therapy for restoration of a healthy intestinal community following disruption.
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  • Chaperonins Resculpt Folding Free Energy Landscapes To Avoid Kinetic Traps and Accelerate Protein Folding
    [Jun 2014]

    Publication date: Available online 5 June 2014
    Source:Journal of Molecular Biology

    Author(s): Xin Zhang , Jeffery W. Kelly







    Categories: Journal Articles
  • Crystal Structures of Ricin Toxin’s Enzymatic Subunit (RTA) in Complex with Neutralizing and Non-neutralizing Single Chain Antibodies
    [Jun 2014]

    Publication date: Available online 4 June 2014
    Source:Journal of Molecular Biology

    Author(s): Michael J. Rudolph , David J. Vance , Jonah Cheung , Matthew C. Franklin , Fiana Burshteyn , Michael S. Cassidy , Ebony N. Gary , Cristina Herrera , Charles B. Shoemaker , Nicholas J. Mantis

    Ricin is a Select Agent Toxin and a member of the RNA N-glycosidase family of medically important plant and bacterial ribosome-inactivating proteins (RIPs). In this study, we determined x-ray crystal structures of the enzymatic subunit of ricin (RTA) in complex with the antigen binding domains (VHH) of five unique single-chain monoclonal antibodies that differ in their respective toxin-neutralizing activities. None of the VHHs made direct contact with residues involved in RTA’s RNA N-glycosidase activity or induced notable allosteric changes in the toxin’s subunit. Rather, the five VHHs had overlapping structural epitopes on the surface of the toxin and differed in the degree to which they made contact with prominent structural elements in two folding domains of the RTA. In general, RTA interactions were influenced most by the VHH CDR3 elements, with the most potent neutralizing antibody having the shortest and most conformationally constrained CDR3. These structures provide unique insights into the mechanisms underlying toxin neutralization and provide critically important information required for the rational design of ricin toxin subunit vaccines.
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    Categories: Journal Articles
  • Chromatin Structure and Replication Origins: Determinants Of Chromosome Replication And Nuclear Organization
    [Jun 2014]

    Publication date: Available online 3 June 2014
    Source:Journal of Molecular Biology

    Author(s): Owen K. Smith , Mirit I. Aladjem

    The DNA replication program is, in part, determined by the epigenetic landscape that governs local chromosome architecture and directs chromosome duplication. Replication must coordinate with other biochemical processes occurring concomitantly on chromatin, such as transcription and remodeling, to insure accurate duplication of both genetic and epigenetic features and to preserve genomic stability. The importance of genome architecture and chromatin looping in coordinating cellular processes on chromatin is illustrated by two recent sets of discoveries. First, chromatin-associated proteins that are not part of the core replication machinery were shown to affect the timing of DNA replication. These chromatin-associated proteins could be working in concert, or perhaps in competition, with the transcriptional machinery and with chromatin modifiers to determine the spatial and temporal organization of replication initiation events. Second, epigenetic interactions are mediated by DNA sequences that determine chromosomal replication. In this review we summarize recent findings and current models linking spatial and temporal regulation of the replication program with epigenetic signaling. We discuss these issues in the context of the genome’s three-dimensional structure with an emphasis on events occurring during the initiation of DNA replication.
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    Categories: Journal Articles
  • Reshaping chromatin after DNA damage: the choreography of histone proteins
    [Jun 2014]

    Publication date: Available online 1 June 2014
    Source:Journal of Molecular Biology

    Author(s): Sophie E. Polo

    DNA damage signaling and repair machineries operate in a nuclear environment, where DNA is wrapped around histone proteins and packaged into chromatin. Understanding how chromatin structure is restored together with the DNA sequence during DNA damage repair has been a topic of intense research. Indeed, chromatin integrity is central to cell functions and identity. Yet, chromatin shows remarkable plasticity in response to DNA damage. This review presents our current knowledge of chromatin dynamics in the mammalian cell nucleus in response to DNA-double strand breaks and UV lesions. I provide an overview of the key players involved in regulating histone dynamics in damaged chromatin regions, focusing on histone chaperones and their concerted action with histone modifiers, chromatin remodelers and repair factors. I also discuss how these dynamics contribute to reshaping chromatin and, by altering the chromatin landscape, may affect the maintenance of epigenetic information.
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    Categories: Journal Articles