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Genes, Volume 6, Issue 2 (June 2015) , Pages 150-450

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Open AccessArticle
Arrest of Viral Proliferation by Ectopic Copies of Its Cognate Replication Origin
Genes 2015, 6(2), 436-450; https://doi.org/10.3390/genes6020436
Received: 7 April 2015 / Revised: 10 June 2015 / Accepted: 18 June 2015 / Published: 23 June 2015
Viewed by 1670 | PDF Full-text (1103 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The initiation step of DNA replication is the crucial determinant of proliferation in all organisms. This step depends on the specific interaction of DNA sequences present at origins of DNA replication and their cognate activators. We wished to explore the hypothesis that the [...] Read more.
The initiation step of DNA replication is the crucial determinant of proliferation in all organisms. This step depends on the specific interaction of DNA sequences present at origins of DNA replication and their cognate activators. We wished to explore the hypothesis that the presence of ectopic origin copies may interfere with proper genome duplication. Bacteriophage λ was used as a model system. To this end, the outcome of an infection of an E. coli strain harboring ectopic copies of the λ origin region was analyzed. By measuring the effect on the host growth, viral production, and electro-microscopic visualization of the resulting λ replicative intermediates, we concluded that the ectopic copies had prevented the normal initiation step of λ DNA replication. These results suggest that DNA decoys encoding viral origins could constitute effective tools to specifically arrest viral proliferation. Full article
(This article belongs to the Special Issue DNA Replication)
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Open AccessReview
Hedgehog Signaling during Appendage Development and Regeneration
Genes 2015, 6(2), 417-435; https://doi.org/10.3390/genes6020417
Received: 4 April 2015 / Revised: 28 May 2015 / Accepted: 5 June 2015 / Published: 23 June 2015
Cited by 12 | Viewed by 3069 | PDF Full-text (1578 KB) | HTML Full-text | XML Full-text
Abstract
Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. [...] Read more.
Regulatory networks that govern embryonic development have been well defined. While a common hypothesis supports the notion that the embryonic regulatory cascades are reexpressed following injury and tissue regeneration, the mechanistic regulatory pathways that mediate the regenerative response in higher organisms remain undefined. Relative to mammals, lower vertebrates, including zebrafish and newts, have a tremendous regenerative capacity to repair and regenerate a number of organs including: appendages, retina, heart, jaw and nervous system. Elucidation of the pathways that govern regeneration in these lower organisms may provide cues that will enhance the capacity for the regeneration of mammalian organs. Signaling pathways, such as the hedgehog pathway, have been shown to play critical functions during development and during regeneration in lower organisms. These signaling pathways have been shown to modulate multiple processes including cellular origin, positional identity and cellular maturation. The present review will focus on the cellular and molecular regulation of the hedgehog (HH) signaling pathway and its interaction with other signaling factors during appendage development and regeneration. Full article
(This article belongs to the Special Issue Hedgehog Signaling Gene Regulatory Networks)
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Open AccessArticle
MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise
Genes 2015, 6(2), 399-416; https://doi.org/10.3390/genes6020399
Received: 26 March 2015 / Revised: 11 June 2015 / Accepted: 18 June 2015 / Published: 23 June 2015
Cited by 14 | Viewed by 2878 | PDF Full-text (221 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
MicroRNA (miRNA) are a class of non-coding, 19–25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic [...] Read more.
MicroRNA (miRNA) are a class of non-coding, 19–25 nucleotide RNA critical for network-level regulation of gene expression. miRNA serve as paracrine signaling molecules. Using an unbiased array approach, we previously identified elevated levels of miR-224 and miR-103 to be associated with a monogenic form of diabetes; HNF1A-MODY. miR-224 is a novel miRNA in the field of diabetes. We sought to explore the role of miR-224 as a potential biomarker in diabetes, and whether such diabetes-associated-miRNA can also be detected in the urine of patients. Absolute levels of miR-224 and miR-103 were determined in the urine of n = 144 individuals including carriers of a HNF1A mutation, participants with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and normal controls. Expression levels were correlated with clinical and biochemical parameters. miR-224 was significantly elevated in the urine of carriers of a HNF1A mutation and participants with T1DM. miR-103 was highly expressed in urine across all diabetes cohorts when compared to controls. For both miR-224 and-103, we found a significant correlation between serum and urine levels (p < 0.01). We demonstrate that miRNA can be readily detected in the urine independent of clinical indices of renal dysfunction. We surmise that the differential expression levels of miR-224 in both HNF1A-MODY mutation carriers and T1DM may be an attempt to compensate for beta-cell demise. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
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Open AccessReview
Alternative Okazaki Fragment Ligation Pathway by DNA Ligase III
Genes 2015, 6(2), 385-398; https://doi.org/10.3390/genes6020385
Received: 31 March 2015 / Revised: 10 June 2015 / Accepted: 18 June 2015 / Published: 23 June 2015
Cited by 6 | Viewed by 2397 | PDF Full-text (227 KB) | HTML Full-text | XML Full-text
Abstract
Higher eukaryotes have three types of DNA ligases: DNA ligase 1 (Lig1), DNA ligase 3 (Lig3) and DNA ligase 4 (Lig4). While Lig1 and Lig4 are present in all eukaryotes from yeast to human, Lig3 appears sporadically in evolution and is uniformly present [...] Read more.
Higher eukaryotes have three types of DNA ligases: DNA ligase 1 (Lig1), DNA ligase 3 (Lig3) and DNA ligase 4 (Lig4). While Lig1 and Lig4 are present in all eukaryotes from yeast to human, Lig3 appears sporadically in evolution and is uniformly present only in vertebrates. In the classical, textbook view, Lig1 catalyzes Okazaki-fragment ligation at the DNA replication fork and the ligation steps of long-patch base-excision repair (BER), homologous recombination repair (HRR) and nucleotide excision repair (NER). Lig4 is responsible for DNA ligation at DNA double strand breaks (DSBs) by the classical, DNA-PKcs-dependent pathway of non-homologous end joining (C-NHEJ). Lig3 is implicated in a short-patch base excision repair (BER) pathway, in single strand break repair in the nucleus, and in all ligation requirements of the DNA metabolism in mitochondria. In this scenario, Lig1 and Lig4 feature as the major DNA ligases serving the most essential ligation needs of the cell, while Lig3 serves in the cell nucleus only minor repair roles. Notably, recent systematic studies in the chicken B cell line, DT40, involving constitutive and conditional knockouts of all three DNA ligases individually, as well as of combinations thereof, demonstrate that the current view must be revised. Results demonstrate that Lig1 deficient cells proliferate efficiently. Even Lig1/Lig4 double knockout cells show long-term viability and proliferate actively, demonstrating that, at least in DT40, Lig3 can perform all ligation reactions of the cellular DNA metabolism as sole DNA ligase. Indeed, in the absence of Lig1, Lig3 can efficiently support semi-conservative DNA replication via an alternative Okazaki-fragment ligation pathway. In addition, Lig3 can back up NHEJ in the absence of Lig4, and can support NER and HRR in the absence of Lig1. Supporting observations are available in less elaborate genetic models in mouse cells. Collectively, these observations raise Lig3 from a niche-ligase to a universal DNA ligase, which can potentially substitute or backup the repair and replication functions of all other DNA ligases in the cell nucleus. Thus, the old model of functionally dedicated DNA ligases is now replaced by one in which only Lig4 remains dedicated to C-NHEJ, with Lig1 and Lig3 showing an astounding functional flexibility and interchangeability for practically all nuclear ligation functions. The underlying mechanisms of Lig3 versus Lig1 utilization in DNA repair and replication are expected to be partly different and remain to be elucidated. Full article
(This article belongs to the Special Issue DNA Replication)
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Open AccessReview
Genetics of Type 2 Diabetes and Clinical Utility
Genes 2015, 6(2), 372-384; https://doi.org/10.3390/genes6020372
Received: 16 April 2015 / Revised: 2 June 2015 / Accepted: 11 June 2015 / Published: 23 June 2015
Cited by 16 | Viewed by 2471 | PDF Full-text (107 KB) | HTML Full-text | XML Full-text
Abstract
A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may [...] Read more.
A large proportion of heritability of type 2 diabetes (T2D) has been attributed to inherent genetics. Recent genetic studies, especially genome-wide association studies (GWAS), have identified a multitude of variants associated with T2D. It is thus reasonable to question if these findings may be utilized in a clinical setting. Here we briefly review the identification of risk loci for T2D and discuss recent efforts and propose future work to utilize these loci in clinical setting—for the identification of individuals who are at particularly high risks of developing T2D and for the stratification of specific health-care approaches for those who would benefit most from such interventions. Full article
(This article belongs to the Special Issue Genetics of Diabetes)
Open AccessReview
The Fork in the Road: Histone Partitioning During DNA Replication
Genes 2015, 6(2), 353-371; https://doi.org/10.3390/genes6020353
Received: 1 May 2015 / Revised: 15 June 2015 / Accepted: 16 June 2015 / Published: 23 June 2015
Cited by 19 | Viewed by 2344 | PDF Full-text (128 KB) | HTML Full-text | XML Full-text
Abstract
In the following discussion the distribution of histones at the replication fork is examined, with specific attention paid to the question of H3/H4 tetramer "splitting." After a presentation of early experiments surrounding this topic, more recent contributions are detailed. The implications of these [...] Read more.
In the following discussion the distribution of histones at the replication fork is examined, with specific attention paid to the question of H3/H4 tetramer "splitting." After a presentation of early experiments surrounding this topic, more recent contributions are detailed. The implications of these findings with respect to the transmission of histone modifications and epigenetic models are also addressed. Full article
(This article belongs to the Special Issue Chromatin Dynamics)
Open AccessReview
PHF6 Degrees of Separation: The Multifaceted Roles of a Chromatin Adaptor Protein
Genes 2015, 6(2), 325-352; https://doi.org/10.3390/genes6020325
Received: 30 April 2015 / Revised: 12 June 2015 / Accepted: 16 June 2015 / Published: 19 June 2015
Cited by 10 | Viewed by 2854 | PDF Full-text (1077 KB) | HTML Full-text | XML Full-text
Abstract
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in [...] Read more.
The importance of chromatin regulation to human disease is highlighted by the growing number of mutations identified in genes encoding chromatin remodeling proteins. While such mutations were first identified in severe developmental disorders, or in specific cancers, several genes have been implicated in both, including the plant homeodomain finger protein 6 (PHF6) gene. Indeed, germline mutations in PHF6 are the cause of the Börjeson–Forssman–Lehmann X-linked intellectual disability syndrome (BFLS), while somatic PHF6 mutations have been identified in T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Studies from different groups over the last few years have made a significant impact towards a functional understanding of PHF6 protein function. In this review, we summarize the current knowledge of PHF6 with particular emphasis on how it interfaces with a distinct set of interacting partners and its functional roles in the nucleoplasm and nucleolus. Overall, PHF6 is emerging as a key chromatin adaptor protein critical to the regulation of neurogenesis and hematopoiesis. Full article
(This article belongs to the Special Issue Chromatin Dynamics)
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Open AccessReview
Chromatin Remodelers: From Function to Dysfunction
Genes 2015, 6(2), 299-324; https://doi.org/10.3390/genes6020299
Received: 30 April 2015 / Revised: 1 June 2015 / Accepted: 3 June 2015 / Published: 12 June 2015
Cited by 37 | Viewed by 4579 | PDF Full-text (1433 KB) | HTML Full-text | XML Full-text
Abstract
Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn [...] Read more.
Chromatin remodelers are key players in the regulation of chromatin accessibility and nucleosome positioning on the eukaryotic DNA, thereby essential for all DNA dependent biological processes. Thus, it is not surprising that upon of deregulation of those molecular machines healthy cells can turn into cancerous cells. Even though the remodeling enzymes are very abundant and a multitude of different enzymes and chromatin remodeling complexes exist in the cell, the particular remodeling complex with its specific nucleosome positioning features must be at the right place at the right time in order to ensure the proper regulation of the DNA dependent processes. To achieve this, chromatin remodeling complexes harbor protein domains that specifically read chromatin targeting signals, such as histone modifications, DNA sequence/structure, non-coding RNAs, histone variants or DNA bound interacting proteins. Recent studies reveal the interaction between non-coding RNAs and chromatin remodeling complexes showing importance of RNA in remodeling enzyme targeting, scaffolding and regulation. In this review, we summarize current understanding of chromatin remodeling enzyme targeting to chromatin and their role in cancer development. Full article
(This article belongs to the Special Issue Chromatin Dynamics)
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Open AccessReview
Replication Stress in Mammalian Cells and Its Consequences for Mitosis
Genes 2015, 6(2), 267-298; https://doi.org/10.3390/genes6020267
Received: 14 April 2015 / Revised: 15 May 2015 / Accepted: 18 May 2015 / Published: 22 May 2015
Cited by 34 | Viewed by 4628 | PDF Full-text (1362 KB) | HTML Full-text | XML Full-text
Abstract
The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can [...] Read more.
The faithful transmission of genetic information to daughter cells is central to maintaining genomic stability and relies on the accurate and complete duplication of genetic material during each cell cycle. However, the genome is routinely exposed to endogenous and exogenous stresses that can impede the progression of replication. Such replication stress can be an early cause of cancer or initiate senescence. Replication stress, which primarily occurs during S phase, results in consequences during mitosis, jeopardizing chromosome segregation and, in turn, genomic stability. The traces of replication stress can be detected in the daughter cells during G1 phase. Alterations in mitosis occur in two types: 1) local alterations that correspond to breaks, rearrangements, intertwined DNA molecules or non-separated sister chromatids that are confined to the region of the replication dysfunction; 2) genome-wide chromosome segregation resulting from centrosome amplification (although centrosomes do not contain DNA), which amplifies the local replication stress to the entire genome. Here, we discuss the endogenous causes of replication perturbations, the mechanisms of replication fork restart and the consequences for mitosis, chromosome segregation and genomic stability. Full article
(This article belongs to the Special Issue DNA Replication)
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Open AccessArticle
An Inactive Geminin Mutant That Binds Cdt1
Genes 2015, 6(2), 252-266; https://doi.org/10.3390/genes6020252
Received: 31 March 2015 / Revised: 24 April 2015 / Accepted: 28 April 2015 / Published: 15 May 2015
Cited by 5 | Viewed by 2253 | PDF Full-text (433 KB) | HTML Full-text | XML Full-text
Abstract
The initiation of DNA replication is tightly regulated in order to ensure that the genome duplicates only once per cell cycle. In vertebrate cells, the unstable regulatory protein Geminin prevents a second round of DNA replication by inhibiting the essential replication factor Cdt1. [...] Read more.
The initiation of DNA replication is tightly regulated in order to ensure that the genome duplicates only once per cell cycle. In vertebrate cells, the unstable regulatory protein Geminin prevents a second round of DNA replication by inhibiting the essential replication factor Cdt1. Cdt1 recruits mini-chromosome maintenance complex (MCM2-7), the replication helicase, into the pre-replication complex (pre-RC) at origins of DNA replication. The mechanism by which Geminin inhibits MCM2-7 loading by Cdt1 is incompletely understood. The conventional model is that Geminin sterically hinders a direct physical interaction between Cdt1 and MCM2-7. Here, we describe an inactive missense mutant of Geminin, GemininAWA, which binds to Cdt1 with normal affinity yet is completely inactive as a replication inhibitor even when added in vast excess. In fact, GemininAWA can compete with GemininWT for binding to Cdt1 and prevent it from inhibiting DNA replication. GemininAWA does not inhibit the loading of MCM2-7 onto DNA in vivo, and in the presence of GemininAWA, nuclear DNA is massively over-replicated within a single S phase. We conclude that Geminin does not inhibit MCM loading by simple steric interference with a Cdt1-MCM2-7 interaction but instead works by a non-steric mechanism, possibly by inhibiting the histone acetyltransferase HBO1. Full article
(This article belongs to the Special Issue DNA Replication)
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Open AccessArticle
JAG: A Computational Tool to Evaluate the Role of Gene-Sets in Complex Traits
Genes 2015, 6(2), 238-251; https://doi.org/10.3390/genes6020238
Received: 20 November 2014 / Accepted: 27 April 2015 / Published: 14 May 2015
Cited by 7 | Viewed by 2736 | PDF Full-text (633 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Gene-set analysis has been proposed as a powerful tool to deal with the highly polygenic architecture of complex traits, as well as with the small effect sizes typically found in GWAS studies for complex traits. We developed a tool, Joint Association of Genetic [...] Read more.
Gene-set analysis has been proposed as a powerful tool to deal with the highly polygenic architecture of complex traits, as well as with the small effect sizes typically found in GWAS studies for complex traits. We developed a tool, Joint Association of Genetic variants (JAG), which can be applied to Genome Wide Association (GWA) data and tests for the joint effect of all single nucleotide polymorphisms (SNPs) located in a user-specified set of genes or biological pathway. JAG assigns SNPs to genes and incorporates self-contained and/or competitive tests for gene-set analysis. JAG uses permutation to evaluate gene-set significance, which implicitly controls for linkage disequilibrium, sample size, gene size, the number of SNPs per gene and the number of genes in the gene-set. We conducted a power analysis using the Wellcome Trust Case Control Consortium (WTCCC) Crohn’s disease data set and show that JAG correctly identifies validated gene-sets for Crohn’s disease and has more power than currently available tools for gene-set analysis. JAG is a powerful, novel tool for gene-set analysis, and can be freely downloaded from the CTG Lab website. Full article
(This article belongs to the Section Technologies and Resources for Genetics)
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Open AccessReview
Genetic Mosaics and the Germ Line Lineage
Genes 2015, 6(2), 216-237; https://doi.org/10.3390/genes6020216
Received: 24 February 2015 / Revised: 27 March 2015 / Accepted: 7 April 2015 / Published: 17 April 2015
Cited by 9 | Viewed by 3001 | PDF Full-text (681 KB) | HTML Full-text | XML Full-text
Abstract
Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans. De novo mutations act as cell markers, allowing the tracing of developmental trajectories of all descendants of the cell in which the new mutation arises. De novo [...] Read more.
Genetic mosaics provide information about cellular lineages that is otherwise difficult to obtain, especially in humans. De novo mutations act as cell markers, allowing the tracing of developmental trajectories of all descendants of the cell in which the new mutation arises. De novo mutations may arise at any time during development but are relatively rare. They have usually been observed through medical ascertainment, when the mutation causes unusual clinical signs or symptoms. Mutational events can include aneuploidies, large chromosomal rearrangements, copy number variants, or point mutations. In this review we focus primarily on the analysis of point mutations and their utility in addressing questions of germ line versus somatic lineages. Genetic mosaics demonstrate that the germ line and soma diverge early in development, since there are many examples of combined somatic and germ line mosaicism for de novo mutations. The occurrence of simultaneous mosaicism in both the germ line and soma also shows that the germ line is not strictly clonal but arises from at least two, and possibly multiple, cells in the embryo with different ancestries. Whole genome or exome DNA sequencing technologies promise to expand the range of studies of genetic mosaics, as de novo mutations can now be identified through sequencing alone in the absence of a medical ascertainment. These technologies have been used to study mutation patterns in nuclear families and in monozygotic twins, and in animal model developmental studies, but not yet for extensive cell lineage studies in humans. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Open AccessArticle
Screening for Mutations in ABCC8 and KCNJ11 Genes in Saudi Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) Patients
Genes 2015, 6(2), 206-215; https://doi.org/10.3390/genes6020206
Received: 16 June 2014 / Revised: 4 March 2015 / Accepted: 13 March 2015 / Published: 13 April 2015
Cited by 1 | Viewed by 2090 | PDF Full-text (105 KB) | HTML Full-text | XML Full-text
Abstract
The autosomal recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is associated with mutations in either ABCC8 or KCNJ11 genes. In the present study, we describe the clinical features and results of genetic analysis of 13 Saudi Arabian patients with PHHI. Clinically, [...] Read more.
The autosomal recessive form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is associated with mutations in either ABCC8 or KCNJ11 genes. In the present study, we describe the clinical features and results of genetic analysis of 13 Saudi Arabian patients with PHHI. Clinically, most patients presented with infantile seizures and/or developmental delay, with a subset of patients who were also found to have abnormal brain imaging and electrophysiological studies. Interestingly no coding pathogenic mutations were identified in these two genes by direct sequencing. However, two splice variants were identified in ABCC8 gene in two patients, and a large deletion of exons 1-22 of the ABCC8 gene was identified in three patients. Our data shows that large deletions in ABCC8 gene are the common genetic mechanism in the Saudi population. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
Open AccessReview
EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression
Genes 2015, 6(2), 185-205; https://doi.org/10.3390/genes6020185
Received: 24 February 2015 / Revised: 19 March 2015 / Accepted: 23 March 2015 / Published: 31 March 2015
Cited by 31 | Viewed by 3699 | PDF Full-text (516 KB) | HTML Full-text | XML Full-text
Abstract
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high [...] Read more.
DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression. The biomarker for defective DNA MMR is microsatellite instability-high (MSI-H), observed in ~15% of colorectal cancers, and defined by mono- and dinucleotide microsatellite frameshift mutations. MSI-H is highly correlated with loss of MMR protein expression, is commonly diploid, is often located in the right side of the colon, prognosticates good patient outcome, and predicts poor efficacy with 5-fluorouracil treatment. Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is another form of MSI at tetranucleotide repeats that has been observed in multiple cancers, but its etiology and clinical relevance to patient care has only been recently illuminated. Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSβ, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6. Tumor hypoxia may also be a contributor. Patients with EMAST colorectal cancers show diminished prognosis compared to patients without the presence of EMAST in their cancer. In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy. Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3. Full article
(This article belongs to the Special Issue Microsatellite Instability)
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Open AccessReview
Nuclear Export of Messenger RNA
Genes 2015, 6(2), 163-184; https://doi.org/10.3390/genes6020163
Received: 30 January 2015 / Revised: 23 March 2015 / Accepted: 24 March 2015 / Published: 31 March 2015
Cited by 25 | Viewed by 4538 | PDF Full-text (13598 KB) | HTML Full-text | XML Full-text
Abstract
Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an essential step of eukaryotic gene expression. In the cell nucleus, a precursor mRNA undergoes a series of processing steps, including capping at the 5' ends, splicing and cleavage/polyadenylation at the [...] Read more.
Transport of messenger RNA (mRNA) from the nucleus to the cytoplasm is an essential step of eukaryotic gene expression. In the cell nucleus, a precursor mRNA undergoes a series of processing steps, including capping at the 5' ends, splicing and cleavage/polyadenylation at the 3' ends. During this process, the mRNA associates with a wide variety of proteins, forming a messenger ribonucleoprotein (mRNP) particle. Association with factors involved in nuclear export also occurs during transcription and processing, and thus nuclear export is fully integrated into mRNA maturation. The coupling between mRNA maturation and nuclear export is an important mechanism for providing only fully functional and competent mRNA to the cytoplasmic translational machinery, thereby ensuring accuracy and swiftness of gene expression. This review describes the molecular mechanism of nuclear mRNA export mediated by the principal transport factors, including Tap-p15 and the TREX complex. Full article
(This article belongs to the Special Issue Mechanisms of mRNA Nuclear Export)
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Open AccessDiscussion
Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification
Genes 2015, 6(2), 150-162; https://doi.org/10.3390/genes6020150
Received: 30 November 2014 / Revised: 4 March 2015 / Accepted: 23 March 2015 / Published: 30 March 2015
Cited by 4 | Viewed by 3325 | PDF Full-text (2747 KB) | HTML Full-text | XML Full-text
Abstract
Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a [...] Read more.
Inherited mutations in the DNA mismatch repair genes (MMR) can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI) is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants) are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review. Full article
(This article belongs to the Special Issue Microsatellite Instability)
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