A large number of mutations in genes that encode RNA binding proteins cause human disease. Many of these RNA binding proteins mediate key steps in post-transcriptional regulation of gene expression ...from mRNA processing to eventual decay in the cytoplasm. Surprisingly, these RNA binding proteins, which are ubiquitously expressed and play fundamental roles in gene expression, are often altered in tissue-specific disease. Mutations linked to disease impact nearly every post-transcriptional processing step and cause diverse disease phenotypes in a variety of specific tissues. This review summarizes steps in post-transcriptional regulation of gene expression that have been linked to disease providing specific examples of some of the many genes affected. Finally, recent advances that hold promise for treatment of some of these diseases are presented.
During the academic year 2020‐2021, the Biology Department at Emory University conducted a faculty search that was designed to continue the success of the department in building an inclusive ...department. There were several actions taken to ensure an equitable search process despite the challenges and biases inherent in search processes that were likely further exacerbated by a raging global pandemic.
The search was approved for two tenure track faculty positions with no formal limitation on the academic rank of the hires. The whole department invested in efforts to have a very broad search that would have the highest likelihood of identifying and recruiting outstanding scientists with a commitment to teaching who also showed evidence of actions toward the mission of diversity, equity, and inclusion.
For this search, we modified aspects of our traditional search in several ways that included the strategy for the search, the ad that described the position, the composition of the search committee, which was expanded to include trainee members, and aspects of the process (performed largely virtually due to COVID‐19). We were fortunate to have strong support from leadership at all levels from the Department to the Dean and Dean’s Office to allow us to make changes aligned with the goals of the search.
A successful search takes a great deal of time and effort dedicated from the search committee as well as all members of the department. The input from trainees, which was new to our process, was invaluable. We will seek to incorporate some of the lessons learned during this recent experience in future searches, with the caveat that we all hope to hold future searches in person. However, there are aspects of the virtual process that may enhance equity and, thus, should be considered for the future. Each search is unique with distinct challenges and opportunities, but there are concrete actions we can take to mitigate bias in the process.
Mechanisms Regulating Protein Localization Bauer, Nicholas C.; Doetsch, Paul W.; Corbett, Anita H.
Traffic (Copenhagen, Denmark),
October 2015, Letnik:
16, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Cellular functions are dictated by protein content and activity. There are numerous strategies to regulate proteins varying from modulating gene expression to post‐translational modifications. One ...commonly used mode of regulation in eukaryotes is targeted localization. By specifically redirecting the localization of a pool of existing protein, cells can achieve rapid changes in local protein function. Eukaryotic cells have evolved elegant targeting pathways to direct proteins to the appropriate cellular location or locations. Here, we provide a general overview of these localization pathways, with a focus on nuclear and mitochondrial transport, and present a survey of the evolutionarily conserved regulatory strategies identified thus far. We end with a description of several specific examples of proteins that exploit localization as an important mode of regulation.
One rapid and efficient mechanism for regulation of protein function is targeted localization. Moving an active protein into a target compartment avoids the expensive need for new protein synthesis. Furthermore, this mode of regulation is rapidly reversible. This review provides an overview of intracellular targeting pathways and then presents mechanisms by which regulation of localization is achieved. Pathways covered in detail include nucleocytoplasmic and mitochondrial transport with more general overviews of chloroplast, peroxisomal, ciliary, endomembrane and vesicular transport.
DNA damage is a natural hazard of life. The most common DNA lesions are base, sugar, and single-strand break damage resulting from oxidation, alkylation, deamination, and spontaneous hydrolysis. If ...left unrepaired, such lesions can become fixed in the genome as permanent mutations. Thus, evolution has led to the creation of several highly conserved, partially redundant pathways to repair or mitigate the effects of DNA base damage. The biochemical mechanisms of these pathways have been well characterized and the impact of this work was recently highlighted by the selection of Tomas Lindahl, Aziz Sancar and Paul Modrich as the recipients of the 2015 Nobel Prize in Chemistry for their seminal work in defining DNA repair pathways. However, how these repair pathways are regulated and interconnected is still being elucidated. This review focuses on the classical base excision repair and strand incision pathways in eukaryotes, considering both Saccharomyces cerevisiae and humans, and extends to some important questions and challenges facing the field of DNA base damage repair.
The RNA exosome is an evolutionarily conserved, ribonuclease complex that is critical for both processing and degradation of a variety of RNAs. Cofactors that associate with the RNA exosome likely ...dictate substrate specificity for this complex. Recently, mutations in genes encoding both structural subunits of the RNA exosome and its cofactors have been linked to human disease. Mutations in the RNA exosome genes
and
cause pontocerebellar hypoplasia type 1b (PCH1b) and type 1c (PCH1c), respectively, which are similar autosomal-recessive, neurodegenerative diseases. Mutations in the RNA exosome gene
cause a distinct syndrome with various tissue-specific phenotypes including retinitis pigmentosa and mild intellectual disability. Mutations in genes that encode RNA exosome cofactors also cause tissue-specific diseases with complex phenotypes. How mutations in these genes give rise to distinct, tissue-specific diseases is not clear. In this review, we discuss the role of the RNA exosome complex and its cofactors in human disease, consider the amino acid changes that have been implicated in disease, and speculate on the mechanisms by which exosome gene mutations could underlie dysfunction and disease.
The polyadenylate binding protein 1 (PABPN1) is a ubiquitously expressed RNA binding protein vital for multiple steps in RNA metabolism. Although PABPN1 plays a critical role in the regulation of RNA ...processing, mutation of the gene encoding this ubiquitously expressed RNA binding protein causes a specific form of muscular dystrophy termed oculopharyngeal muscular dystrophy (OPMD). Despite the tissue-specific pathology that occurs in this disease, only recently have studies of PABPN1 begun to explore the role of this protein in skeletal muscle. We have used co-immunoprecipitation and mass spectrometry to identify proteins that interact with PABPN1 in mouse skeletal muscles. Among the interacting proteins we identified Matrin 3 (MATR3) as a novel protein interactor of PABPN1. The MATR3 gene is mutated in a form of distal myopathy and amyotrophic lateral sclerosis (ALS). We demonstrate, that like PABPN1, MATR3 is critical for myogenesis. Furthermore, MATR3 controls critical aspects of RNA processing including alternative polyadenylation and intron retention. We provide evidence that MATR3 also binds and regulates the levels of long non-coding RNA (lncRNA) Neat1 and together with PABPN1 is required for normal paraspeckle function. We demonstrate that PABPN1 and MATR3 are required for paraspeckles, as well as for adenosine to inosine (A to I) RNA editing of Ctn RNA in muscle cells. We provide a functional link between PABPN1 and MATR3 through regulation of a common lncRNA target with downstream impact on paraspeckle morphology and function. We extend our analysis to a mouse model of OPMD and demonstrate altered paraspeckle morphology in the presence of endogenous levels of alanine-expanded PABPN1. In this study, we report protein-binding partners of PABPN1, which could provide insight into novel functions of PABPN1 in skeletal muscle and identify proteins that could be sequestered with alanine-expanded PABPN1 in the nuclear aggregates found in OPMD.
Transport of macromolecules between the cytoplasm and the nucleus is critical for the function of all eukaryotic cells. Large macromolecular channels termed nuclear pore complexes that span the ...nuclear envelope mediate the bidirectional transport of cargoes between the nucleus and cytoplasm. However, the influence of macromolecular trafficking extends past the nuclear pore complex to transcription and RNA processing within the nucleus and signaling pathways that reach into the cytoplasm and beyond. At the Mechanisms of Nuclear Transport biennial meeting held from October 18 to 23, 2013 in Woods Hole, MA, researchers in the field met to report on their recent findings. The work presented highlighted significant advances in understanding nucleocytoplasmic trafficking including how transport receptors and cargoes pass through the nuclear pore complex, the many signaling pathways that impinge on transport pathways, interplay between the nuclear envelope, nuclear pore complexes, and transport pathways, and numerous links between transport pathways and human disease. The goal of this review is to highlight newly emerging themes in nuclear transport and underscore the major questions that are likely to be the focus of future research in the field.
•Summary of the 2013 Mechanisms of Nuclear Transport Meeting•Insights into the overall architecture and function of the nuclear pore complex•Mechanisms by which cargo molecules are transported into and out of the nucleus•Links between the nuclear pore complex and gene expression including mRNA export•Emerging connections between nuclear transport pathways and human disease
Akey et al.1 use complementary experimental approaches and AI-based structure prediction to reveal new details of the structure of the yeast nuclear pore complex, providing key insights into ...evolution, assembly, and nucleocytoplasmic transport mechanisms.
Akey et al.1 use complementary experimental approaches and AI-based structure prediction to reveal new details of the structure of the yeast nuclear pore complex, providing key insights into evolution, assembly, and nucleocytoplasmic transport mechanisms.
The probiotic yeast Saccharomyces boulardii has been shown to ameliorate disease severity in the context of many infectious and inflammatory conditions. However, use of S. boulardii as a prophylactic ...agent or therapeutic delivery vector would require delivery of S. boulardii to a healthy, uninflamed intestine. In contrast to inflamed mucosal tissue, the diverse microbiota, intact epithelial barrier, and fewer inflammatory immune cells within the healthy intestine may all limit the degree to which S. boulardii contacts and influences the host mucosal immune system. Understanding the nature of these interactions is crucial for application of S. boulardii as a prophylactic agent or therapeutic delivery vehicle. In this study, we explore both intrinsic and immunomodulatory properties of S. boulardii in the healthy mucosal immune system. Genomic sequencing and morphological analysis of S. boulardii reveals changes in cell wall components compared to non-probiotic S. cerevisiae that may partially account for probiotic functions of S. boulardii. Flow cytometry and immunohistochemistry demonstrate limited S. boulardii association with murine Peyer's patches. We also show that although S. boulardii induces a systemic humoral immune response, this response is small in magnitude and not directed against S. boulardii itself. RNA-seq of the draining mesenteric lymph nodes indicates that even repeated administration of S. boulardii induces few transcriptional changes in the healthy intestine. Together these data strongly suggest that interaction between S. boulardii and the mucosal immune system in the healthy intestine is limited, with important implications for future work examining S. boulardii as a prophylactic agent and therapeutic delivery vehicle.
The polyadenosine RNA binding protein polyadenylate‐binding nuclear protein 1 (PABPN1) plays key roles in post‐transcriptional processing of RNA. Although PABPN1 is ubiquitously expressed and ...presumably contributes to control of gene expression in all tissues, mutation of the PABPN1 gene causes the disease oculopharyngeal muscular dystrophy (OPMD), in which a limited set of skeletal muscles are affected. A major goal in the field of OPMD research is to understand why mutation of a ubiquitously expressed gene leads to a muscle‐specific disease. PABPN1 plays a well‐documented role in controlling the poly(A) tail length of RNA transcripts but new functions are emerging through studies that exploit a variety of unbiased screens as well as model organisms. This review addresses (a) the molecular function of PABPN1 incorporating recent findings that reveal novel cellular functions for PABPN1 and (b) the approaches that are being used to understand the molecular defects that stem from expression of mutant PABPN1. The long‐term goal in this field of research is to understand the key molecular functions of PABPN1 in muscle as well as the mechanisms that underlie the pathological consequences of mutant PABPN1. Armed with this information, researchers can seek to develop therapeutic approaches to enhance the quality of life for patients afflicted with OPMD.
The polyadenylate‐binding nuclear protein 1 (PABPN1) plays a critical role in gene expression. Although PABPN1 is ubiquitously expressed, a mutation in the PABPN1 gene causes a muscle‐specific disease, oculopharyngeal muscular dystrophy (OPMD). This review addresses both the molecular functions of PABPN1 and the approaches being used to elucidate the mechanisms underlying the muscle‐specific pathogenesis of OPMD.
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