Check out our New Publishers' Select for Free Articles

BBA - Gene Regulatory Mechanisms (v.1819, #6)

Editorial Board (pp. i).

Nuclear transport and RNA processing by Rodriguez-Navarro Susana Rodríguez-Navarro (pp. 467-467).

Nuclear organization and chromatin dynamics in yeast: Biophysical models or biologically driven interactions? by Benjamin Albert; Leger-Silvestre Isabelle Léger-Silvestre; Christophe Normand; Olivier Gadal (pp. 468-481).

Over the past decade, tremendous progress has been made in understanding the spatial organization of genes and chromosomes. Nuclear organization can be thought of as information that is not encoded in DNA, but which nevertheless impacts gene expression. Nuclear organizational influences can be cell-specific and are potentially heritable. Thus, nuclear organization fulfills all the criteria necessary for it to be considered an authentic level of epigenetic information. Chromosomal nuclear organization is primarily dictated by the biophysical properties of chromatin. Diffusion models of polymers confined in the crowded nuclear space accurately recapitulate experimental observation. Diffusion is a Brownian process, which implies that the positions of chromosomes and genes are not defined deterministically but are likely to be dictated by the laws of probability. Despite the small size of their nuclei, budding yeast have been instrumental in discovering how epigenetic information is encoded in the spatial organization of the genome. The relatively simple organization of the yeast nucleus and the very high number of genetically identical cells that can be observed under fluorescent microscopy allow statistically robust definitions of the gene and chromosome positions in the nuclear space to be constructed. In this review, we will focus on how the spatial organization of the chromatin in the yeast nucleus might impact transcription. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► 3D chromatin organization in nuclear space impacts nuclear functions. ► Biophysical models of chromatin accurately recapitulate observed nuclear organization. ► Saccharomyces cerevisiae is a simple model for studying nuclear organization. ► Numerous nuclear landmarks interact with defined chromatin elements. ► Chromatin is organized by global biophysical rules and local biological interactions.

Keywords: Nuclear structure; Chromatin dynamics; Chromatin organization; Nuclear pore complex; Saccharomyces cerevisiae

Intra-nuclear mobility and target search mechanisms of transcription factors: A single-molecule perspective on gene expression by Davide Normanno; Maxime Dahan; Xavier Darzacq (pp. 482-493).

Precise expression of specific genes in time and space is at the basis of cellular viability as well as correct development of organisms. Understanding the mechanisms of gene regulation is fundamental and still one of the great challenges for biology. Gene expression is regulated also by specific transcription factors that recognize and bind to specific DNA sequences. Transcription factors dynamics, and especially the way they sample the nucleoplasmic space during the search for their specific target in the genome, are a key aspect for regulation and it has been puzzling researchers for forty years. The scope of this review is to give a state-of-the-art perspective over the intra-nuclear mobility and the target search mechanisms of specific transcription factors at the molecular level. Going through the seminal biochemical experiments that have raised the first questions about target localization and the theoretical grounds concerning target search processes, we describe the most recent experimental achievements and current challenges in understanding transcription factors dynamics and interactions with DNA using in vitro assays as well as in live prokaryotic and eukaryotic cells. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Transcription of specific genes has fundamental importance in all cellular processes. ► DNA-binding transcription factors are key players in transcription regulation. ► Target search and DNA-binding dictate transcription factor regulation kinetics. ► Intra-nuclear mobility and target search are still elusive and puzzling. ► Direct observation of transcription factors might clarify regulation mechanisms.

Keywords: Target search; Transcription factor; Gene expression regulation; Facilitated diffusion; Single-molecule analysis

To the pore and through the pore: A story of mRNA export kinetics by Marlene Oeffinger; Daniel Zenklusen (pp. 494-506).

The evolutionary ‘decision’ to store genetic information away from the place of protein synthesis, in a separate compartment, has forced eukaryotic cells to establish a system to transport mRNAs from the nucleus to the cytoplasm for translation. To ensure export to be fast and efficient, cells have evolved a complex molecular interplay that is tightly regulated. Over the last few decades, many of the individual players in this process have been described, starting with the composition of the nuclear pore complex to proteins that modulate co-transcriptional events required to prepare an mRNP for export to the cytoplasm. How the interplay between all the factors and processes results in the efficient and selective export of mRNAs from the nucleus and how the export process itself is executed within cells, however, is still not fully understood. Recent advances in using proteomic and single molecule microscopy approaches have provided important insights into the process and its kinetics. This review summarizes these recent advances and how they led to the current view on how cells orchestrate the export of mRNAs. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► The co-transcriptional recruitment of mRNA maturation factors is linked to export. ► mRNPs have to undergo surveillance after transcription and before entry to the pore. ► mRNA transport rates per pore in yeast are about 16 mRNPs per minute. ► Docking and release are the rate-limiting steps of mRNA export through the pore. ► Translocation trough the nuclear pore occurs in tens of milliseconds.

Keywords: mRNA export; Nuclear pore complex; mRNA maturation; Single molecule imaging; Kinetics; mRNP

mRNA export and the TREX complex by Jun Katahira (pp. 507-513).

Over the past few decades, we have learned that eukaryotes have evolved sophisticated means to coordinate the nuclear export of mRNAs with different steps of gene expression. This functional orchestration is important for the maintenance of the efficiency and fidelity of gene expression processes. The TREX (TRanscription-EXport) complex is an evolutionarily conserved multiprotein complex that plays a major role in the functional coupling of different steps during mRNA biogenesis, including mRNA transcription, processing, decay, and nuclear export. Furthermore, recent gene knockout studies in mice have revealed that the metazoan TREX complex is required for cell differentiation and development, likely because this complex regulates the expression of key genes. These newly identified roles for the TREX complex suggest the existence of a relationship between mRNA nuclear biogenesis and more complex cellular processes. This review describes the functional roles of the TREX complex in gene expression and the nuclear export of mRNAs. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Gene expression process is streamlined by the activities of multifunctional proteins. ► The TREX complex couples transcription elongation to mRNA nuclear export. ► Complex cellular activities are regulated by the metazoan TREX complex. ► The molecular mechanism of mRNA export by the TREX complex is discussed.

Keywords: Nucleo-cytoplasmic transport; TREX complex; Transcription; mRNA 3′-end formation; Gene expression

New clues to understand the role of THO and other functionally related factors in mRNP biogenesis by Rosa Luna; Rondon Ana G. Rondón; Andrés Aguilera (pp. 514-520).

Coupling of transcription with mRNA processing and export has been shown to be relevant to efficient gene expression. A number of studies have determined that THO/TREX, a nuclear protein complex conserved from yeast to humans, plays an important role in mRNP biogenesis connecting transcription elongation, mRNA export and preventing genetic instability. Recent data indicates that THO could be relevant to different mRNA processing steps, including the 3′-end formation, transcript release and export. Novel connections of THO to proteins related to the splicing machinery, provide new views about possible functions of THO in mRNP biogenesis. In this review, we summarize the previous and new results concerning the impact of THO in transcription and its biological implications, with a special emphasis on the relationship with THSC/TREX-2 and other functionally related factors involved in mRNA biogenesis and export. The emerging picture presents THO as a dynamic complex interacting with the nascent RNA and with different factors connecting nuclear functions necessary for mRNP biogenesis with genome integrity, cellular homeostasis and development. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► THO is a mRNP factor necessary for the formation of export-competent mRNAs. ► THO/TREX is recruited to all active RNAPII transcribed genes, accumulating towards the 3 ′end. ► THO and THSC/TREX-2 are two key mRNP with a role in the maintenance of genome integrity. ► THO is a dynamic factor transiently interacting with THSC/TREX-2, CIP29/Tho1 and related factors

Keywords: mRNP biogenesis; THO; Sub2; TREX; THSC/TREX-2/RNAPII transcription; mRNA export

Ubiquitin and assembly of export competent mRNP by Anna Babour; Catherine Dargemont; Françoise Stutz (pp. 521-530).

The production of mature and export competent mRNP (mRNA ribonucleoprotein) complexes depends on a series of highly coordinated processing reactions. RNA polymerase II (RNAPII) plays a central role in this process by mediating the sequential recruitment of mRNA maturation and export factors to transcribing genes, thereby establishing a strong functional link between transcription and export through nuclear pore complexes (NPC). Growing evidence indicates that post-translational modifications participate in the dynamic association of processing and export factors with mRNAs ensuring that the transitions and rearrangements undergone by the mRNP occur at the right time and place. This review mainly focuses on the role of ubiquitin conjugation in controlling mRNP assembly and quality control from transcription down to export through the NPC. It emphasizes the central role of ubiquitylation in organizing the chronology of events along this highly dynamic pathway. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Histone H2B ubiquitylation affects late mRNA export events. ► Ubiquitin regulates co-transcriptional recruitment of export factors. ► THO is a platform coordinating mRNP assembly, 3′ end formation and release from transcription sites. ► mRNP surveillance at the pore is linked to an ultimate remodeling step before exit into the cytoplasm. ► Ubiquitylation may regulate multiple aspects of nuclear pore complex structure and function.

Keywords: Ubiquitin; Transcription; mRNP assembly; mRNA export; Quality control; Nuclear pore complex

mRNA export and sumoylation—Lessons from plants by Iris Meier (pp. 531-537).

SUMO is a small ubiquitin-related protein modifier that is involved in a number of biological processes, including transcription, DNA repair, genome stability, and chromatin organization. Its potential role in mRNA biogenesis is less well investigated. The biogenesis of mRNA is closely coupled to transcription as well as mRNA nuclear export and several of the involved proteins have dual roles and appear in several complexes. Recently, SUMO-proteome analyses have discovered a number of these proteins as putative targets of SUMO regulation. In the model plant Arabidopsis thaliana, several mutants as well as environmental conditions have been identified that show a close correlation between over- and under-sumoylation of nuclear proteins and mRNA export retention. Three new plant SUMO-proteome studies add to the list of potentially sumoylated RNA-related proteins. Here, the emerging connection between SUMO and mRNA export is compared across kingdoms and its potential mechanistic role is discussed. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Many mRNA-maturation related proteins are present in SUMO proteomes of yeast, animals and plants. ► Mutations in nucleoporins and different stress treatments affect both sumoylation and mRNA export in plants. ► Nuclear protein sumoylation acts upstream of mRNA export in plants. ► A model is proposed for a role of transient sumoylation in mRNA maturation and export surveillance.

Keywords: Sumoylation; mRNA export; Arabidopsis thaliana; Flowering time; Abiotic stress; Heat shock

Regulated pre-mRNA splicing: The ghostwriter of the eukaryotic genome by Tracy L. Johnson; Josep Vilardell (pp. 538-545).

Intron removal is at the heart of mRNA synthesis. It is mediated by one of the cell's largest complexes, the spliceosome. Yet, the fundamental chemistry involved is simple. In this review we will address how the spliceosome acts in diverse ways to optimize gene expression in order to meet the cell's needs. This is done largely by regulating the splicing of key transcripts encoding products that control gene expression pathways. This widespread role is evident even in the yeast Saccharomyces cerevisiae, where many introns appear to have been lost; yet how this control is being achieved is known only in a few cases. Here we explore the relevant examples and posit hypotheses whereby regulated splicing fine-tunes gene expression pathways to maintain cell homeostasis. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Two simple and consecutive chemical reactions are catalyzed co-trancriptionally by the spliceosome, a large macromolecular complex. ► The spliceosome is essential for generating mature mRNA. ► The cell takes advantage of this to generate different amounts and isoforms of mRNAs, according to its needs. ► In yeast, control of pre-mRNA splicing of critical genes allows the cell to affect all the pathways in gene expression. ► The spliceosome can be both the sensor and controller to fine tune genetic output.

Keywords: Spliceosome; Yra1; Sus1; L30; Mer1; Histone modification

The long and the short of it: The role of the zinc finger polyadenosine RNA binding protein, Nab2, in control of poly(A) tail length by Sharon Soucek; Anita H. Corbett; Milo B. Fasken (pp. 546-554).

In eukaryotic cells, addition of poly(A) tails to transcripts by 3′-end processing/polyadenylation machinery is a critical step in gene expression. The length of the poly(A) tail influences the stability, nuclear export and translation of mRNA transcripts. Control of poly(A) tail length is thus an important mechanism to regulate the abundance and ultimate translation of transcripts. Understanding the global regulation of poly(A) tail length will require dissecting the contributions of enzymes, regulatory factors, and poly(A) binding proteins (Pabs) that all cooperate to regulate polyadenylation. A recent addition to the Pab family is the CCCH-type zinc finger class of Pabs that includes S. cerevisiae Nab2 and its human counterpart, ZC3H14. In S. cerevisiae, Nab2 is an essential nuclear Pab implicated in both poly(A) RNA export from the nucleus and control of poly(A) tail length. Consistent with an important role in regulation of poly(A) tail length, depletion of Nab2 from yeast cells results in hyperadenylation of poly(A) RNA. In this review, we focus on the role of Nab2 in poly(A) tail length control and speculate on potential mechanisms by which Nab2 could regulate poly(A) tail length based on reported physical and genetic interactions. We present models, illustrating how Nab2 could regulate poly(A) tail length by limiting polyadenylation and/or enhancing trimming. Given that mutation of the gene encoding the human Nab2 homologue, ZC3H14, causes a form of autosomal recessive intellectual disability, we also speculate on how mutations in a gene encoding a ubiquitously expressed Pab lead specifically to neurological defects. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Transcript poly(A) tails of correct length are critical for proper gene expression. ► Nab2 is an essential nuclear polyadenosine binding protein in S. cerevisiae. ► Nab2 is important for control of poly(A) tail length of RNA transcripts. ► The Drosophila Nab2 homologue, dNab2, is critical for neuronal function in flies. ► Mutations in the gene encoding human Nab2, ZC3H14, cause intellectual disability.

Keywords: Nab2; ZC3H14; Poly(A) binding protein; Poly(A) tail length control; Polyadenylation; Zinc finger

mRNA export and gene expression: The SAGA–TREX-2 connection by Garcia-Oliver Encar García-Oliver; Garcia-Molinero Varinia García-Molinero; Rodriguez-Navarro Susana Rodríguez-Navarro (pp. 555-565).

In the gene expression field, different steps have been traditionally viewed as discrete and unconnected events. Nowadays, genetic and functional studies support the model of a coupled network of physical and functional connections to carry out mRNA biogenesis. Gene expression is a coordinated process that comprises different linked steps like transcription, RNA processing, export to the cytoplasm, translation and degradation of mRNAs. Its regulation is essential for cellular survival and can occur at many different levels. Transcription is the central function that occurs in the nucleus, and RNAPII plays an essential role in mRNA biogenesis. During transcription, nascent mRNA is associated with the mRNA-binding proteins involved in processing and export of the mRNA particle. Cells have developed a network of multi-protein complexes whose functions regulate the different factors involved both temporally and spatially. This coupling mechanism acts as a quality control to solve some of the organization problems of gene expression in vivo, where all the factors implicated ensure that mRNAs are ready to be exported and translated. In this review, we focus on the functional coupling of gene transcription and mRNA export, and place particular emphasis on the relationship between the NPC-associated complex, TREX2, and the transcription co-activator, SAGA. We have pinpointed the experimental evidence for Sus1's roles in transcription initiation, transcription elongation and mRNA export. In addition, we have reviewed other NPC-related processes such as gene gating to the nuclear envelope, the chromatin structure and the cellular context in which these processes take place. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► The SAGA complex links transcription to mRNA export. ► The TREX-2 complex associates with the NPC and facilitates mRNA export. ► SAGA and TREX-2 are coordinated through Sus1. ► The cellular context impacts on SAGA/TREX-2 coordination.

Keywords: SAGA; TREX-2; Sus1; Proteasome; Nuclear Pore Complex

Nuclear export as a key arbiter of “mRNA identity” in eukaryotes by Alexander F. Palazzo; Abdalla Akef (pp. 566-577).

Over the past decade, various studies have indicated that most of the eukaryotic genome is transcribed at some level. The pervasiveness of transcription might seem surprising when one considers that only a quarter of the human genome comprises genes (including exons and introns) and less than 2% codes for protein. This conundrum is partially explained by the unique evolutionary pressures that are imposed on species with small population sizes, such as eukaryotes. These conditions promote the expansion of introns and non-functional intergenic DNA, and the accumulation of cryptic transcriptional start sites. As a result, the eukaryotic gene expression machinery must effectively evaluate whether or not a transcript has all the hallmarks of a protein-coding mRNA. If a transcript contains these features, then positive feedback loops are activated to further stimulate its transcription, processing, nuclear export and ultimately, translation. However if a transcript lacks features associated with “mRNA identity”, then the RNA is degraded and/or used to inhibit further transcription and translation of the gene. Here we discuss how mRNA identity is assessed by the nuclear export machinery in order to extract meaningful information from the eukaryotic genome. In the process, we provide an explanation of why certain sequences that are enriched in protein-coding genes, such as the signal sequence coding region, promote mRNA nuclear export in vertebrates. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.Display Omitted► Eukaryotes have elevated levels of spurious transcription from intergenic regions. ► Eukaryotes must ensure that only protein-coding mRNAs undergo nuclear export. ► Through a coupling network, export factors evaluate mRNA identity features. ► The signal sequence coding region is an mRNA identity element for nuclear export. ► Gradients of GC-content may also serve as general mRNA identity features.

Keywords: Abbreviations; ALREX; (Alternative mRNA Export); CBC; (Cap Binding Complex); CTD; (Carboxy-Terminal Domain); EJC; (Exon Junction Complex); mRNP; (Messenger Ribonucleoprotein); MSCR; (Mitochondrial Targeting Sequence Coding Region); NPC; (Nuclear Pore Complex); Pol II; (RNA Polymerase II); TREX; (Transcription Export); SR; (Serine/Arginine-Rich); SSCR; (Signal Sequence Coding Region); UAS; (Upstream Activating Sequence)mRNA export; mRNA identity; Coupling; TREX; SSCR; ALREX

Structural basis for the assembly and disassembly of mRNA nuclear export complexes by Eugene Valkov; Jack C. Dean; Divyang Jani; Sonja I. Kuhlmann; Murray Stewart (pp. 578-592).

Most of the individual components of the nuclear elements of the gene expression pathway have been identified and high-resolution structural information is becoming available for many of them. Information is also starting to become available on the larger complexes they form and is beginning to give clues about how the dynamics of their interactions generate function. Although the translocation of export-competent messenger ribonucleoprotein particles (mRNPs) through the nuclear pore transport channel that is mediated by interactions with nuclear pore proteins (nucleoporins) is relatively well understood, the precise molecular mechanisms underlying the assembly of export-competent mRNPs in the nucleus and their Dbp5-mediated disassembly in the cytoplasm is less well defined. Considerable information has been obtained on the structure of Dbp5 in its different nucleotide-bound states and in complex with Gle1 or Nup159/NUP214. Although the precise manner by which the Dbp5 ATPase cycle is coupled to mRNP remodelling remains to be established, current models capture many key details of this process. The formation of export-competent mRNPs in the nucleus remains an elusive component of this pathway and the precise nature of the remodelling that generates these mRNPs as well as detailed understanding of the molecular mechanisms by which this step is integrated with the transcriptional, splicing and polyadenylation machinery by the TREX and TREX-2 complexes remain obscure. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.►Nuclear mRNA export begins with assembly of an export-competent mRNP in the nucleus. ►Export-competent mRNPs diffuse back-and-forth through nuclear pores. ►Dbp5 removes export factors from mRNPs at the pore's cytoplasmic face, preventing return to the nucleus. ►TREX and TREX-2 link export-competent mRNPs assembly to earlier gene expression pathway steps. ►Emerging structural information is generating a molecular understanding of these processes.

Keywords: mRNA nuclear export; Nuclear export factor; NXF1; Mex67; Dbp5; DEAD-box helicase

Ways and means of eukaryotic mRNA decay by Vidya Balagopal; Lydia Fluch; Tracy Nissan (pp. 593-603).

Messenger RNA degradation is an important point of control for gene expression. Genome-wide studies on mRNA stability have demonstrated its importance in adaptation and stress response. Most of the key players in mRNA decay appear to have been identified. The study of these proteins brings insight into the mechanism of general and specific targeting of transcripts for degradation. Recruitment and assembly of mRNP complexes enhance and bring specificity to mRNA decay. mRNP complexes can form larger structures that have been found to be ubiquitous in nature. Discovery of P-Bodies, an archetype of this sort of aggregates, has generated interest in the question of where mRNA degrades. This is currently an open question under extensive investigation. This review will discuss in detail the recent developments in the regulation of mRNA decay focusing on yeast as a model system. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► mRNA decay is an important determinant of gene expression. ► Discuss insights into gene expression gained from global mRNA decay studies. ► Review the mRNA decay pathways and mechanisms emphasizing studies in yeast. ► Detail recent developments in the mechanism and control of mRNA decapping. ► Discuss the role of mRNPs and higher order aggregates in mRNA degradation.

Keywords: mRNA decay; P-bodies; mRNA turnover; Decapping

Genome-wide studies of mRNA synthesis and degradation in eukaryotes by Perez-Ortin José E. Pérez-Ortín; de Miguel-Jimenez Lola de Miguel-Jiménez; Chavez Sebastián Chávez (pp. 604-615).

In recent years, the use of genome-wide technologies has revolutionized the study of eukaryotic transcription producing results for thousands of genes at every step of mRNA life. The statistical analyses of the results for a single condition, different conditions, different transcription stages, or even between different techniques, is outlining a totally new landscape of the eukaryotic transcription process. Although most studies have been conducted in the yeast Saccharomyces cerevisiae as a model cell, others have also focused on higher eukaryotes, which can also be comparatively analyzed. The picture which emerges is that transcription is a more variable process than initially suspected, with large differences between genes at each stage of the process, from initiation to mRNA degradation, but with striking similarities for functionally related genes, indicating that all steps are coordinately regulated. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► Complementary methodologies allow discrimination among genome-wide transcription features. ► Comparing nascent and mature TR should detect post-transcriptional differences. ► Intragenic distribution of RNA pol II is influenced by nucleosome positioning. ► RNA pol dynamics results from the interplay with chromatin and elongation factors. ► A model: transcriptional and post-transcriptional regulons would be interconnected.

Keywords: Transcription rate; mRNA turnover; RNA polymerase II; Transcription elongation; mRNA stability

Regulated nucleocytoplasmic transport during gametogenesis by Yoichi Miyamoto; Peter R. Boag; Gary R. Hime; Kate L. Loveland (pp. 616-630).

Gametogenesis is the process by which sperm or ova are produced in the gonads. It is governed by a tightly controlled series of gene expression events, with some common and others distinct for males and females. Nucleocytoplasmic transport is of central importance to the fidelity of gene regulation that is required to achieve the precisely regulated germ cell differentiation essential for fertility. In this review we discuss the physiological importance for gamete formation of the molecules involved in classical nucleocytoplasmic protein transport, including importins/karyopherins, Ran and nucleoporins. To address what functions/factors are conserved or specialized for these developmental processes between species, we compare knowledge from mice, flies and worms. The present analysis provides evidence of the necessity for and specificity of each nuclear transport factor and for nucleoporins during germ cell differentiation. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.► The physiological importance of the nuclear transport factors in gametogenesis. ► Comparison of knowledge from mice, flies and worms. ► The insights gained from knockout models that focus on molecules involved in a nuclear transport. ► Discussion of the specificity of each nuclear transport factor during germ cell differentiation.

Keywords: Nuclear transport; Importin/karyopherin; Nuclear pore complex; Spermatogenesis; Oogenesis

Sections

Personal tools

BBA - Gene Regulatory Mechanisms (v.1819, #6)

Sections

Personal tools

Local resources

BBA - Gene Regulatory Mechanisms (v.1819, #6)