When Genome Maintenance Goes Badly Awry.
Ontology highlight
ABSTRACT:
SUBMITTER: Kass EM
PROVIDER: S-EPMC4966655 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
When Genome Maintenance Goes Badly Awry.
Kass Elizabeth M EM Moynahan Mary Ellen ME Jasin Maria M
Molecular cell 20160601 5
Genetic abnormalities are present in all tumor types, although the frequency and type can vary. Chromosome abnormalities include highly aberrant structures, particularly chromothriptic chromosomes. The generation of massive sequencing data has illuminated the scope of the mutational burden in cancer genomes, identifying patterns of mutations (mutation signatures), which have the potential to shed light on the relatedness and etiologies of cancers and impact therapy response. Some mutation patter ...[more]
Similar Datasets
Project description:Desmosomal cadherins constitute the adhesive core of desmosomes. Different desmosomal cadherins are differentially expressed in a tissue-specific as well as differentiation-dependent manner. The skin and the heart are two examples of tissues whose vital functions require the ability to endure mechanical stress, and therefore, rely on the integrity of desmosomal adhesion. When this adhesion is compromised via mutations in genes encoding desmosomal cadherins or associated plaque proteins, both tissues can suffer the consequences. Open questions revolve around whether the resulting phenotypes are solely because of physical disruption of cell adhesion or whether these events are coupled with signaling mechanisms that influence many additional cellular processes. In this review, we focus on new developments in desmosomal adhesion with an emphasis on the skin, hair, and heart.
| S-EPMC4296313 | biostudies-literature
Project description:In the dominant theoretical framework, human communication is modeled as the faithful transmission of information. This implies that when people are involved in communicational exchanges, they should be sensitive to the success with which information is transmitted, easily detecting when conversations lack coherence. The expectation that humans are good at detecting conversational incoherence is in line with common intuition, but there are several reasons to suspect that it might be unrealistic. First, similar intuitions have been shown to be unrealistic for a number of psychological processes. Second, faithful information transmission may conflict with other conversational goals. Third, mechanisms supporting information transmission may themselves lead to cases of incoherence being missed. To ascertain the extent to which people are insensitive to patches of serious conversational incoherence, we generated such patches in the laboratory by repeatedly crossing two unrelated conversations. Across two studies, involving both narrowly and broadly focused conversations, between 27% and 42% of the conversants did not notice that their conversations had been crossed. The results of these studies suggest that it may indeed be unrealistic to model spontaneous conversation as faithful information transmission. Rather, our results are more consistent with models of communication that view it as involving noisy and error-prone inferential processes, serving multiple independent goals.
| S-EPMC4114551 | biostudies-literature
Project description:Age-related chronic inflammatory activation of microglia and their dysfunction are observed in many neurodegenerative diseases, and the potential contributions of these dysfunctional cells to neurodegeneration have been demonstrated recently. The housekeeping and defensive functions of microglia, such as surveying the brain parenchyma and phagocytosis of neuronal debris after injury, are important for brain homeostasis and immunity. During neurodegenerative diseases, loss of these functions can promote disease pathology by producing proinflammatory cytokines and increasing oxidative stress, which can exaggerate the ongoing neuroinflammation. A recent surge in microglial research has unraveled myriads of microglial phenotypes associated with aging and neurodegenerative diseases, in addition to the conventional M1/M2 paradigm. Each of these phenotypes can be characterized by distinct transcriptional profiles as well as altered metabolism, migration, and phagocytosis characteristics. Mutations in triggering receptor expressed on myeloid cells 2 (Trem2) and granulin (GRN) are associated with various neurodegenerative diseases, and these genes are dysregulated in the majority of recently identified microglial phenotypes. These genes act as checkpoint regulators and maintain microglial inflammatory fitness, principally through metabolic modulation. Dysfunctional microglia typically show mitochondrial deficits, glycolysis elevation, and lipid droplet accumulation, which results in reduced migration and phagocytosis and increased proinflammatory cytokine secretion and reactive oxygen species release. In this mini-review article, we discuss the existing data regarding metabolic perturbations in dysfunctional microglia and their documented associations with neurodegeneration, highlighting how aging-induced chronic microglial activation alters microglial bioenergetics, leading to impaired homeostatic and housekeeping functions. Dysfunctional microglia initiate or exacerbate neurodegeneration, and key pathways involved in the dysfunctional processes, including metabolism, may represent potential intervention targets for correcting imbalances.
| S-EPMC7438837 | biostudies-literature
Project description: Not available
| S-EPMC8374567 | biostudies-literature
Project description:Transcription is a complex process that integrates the state of the cell and its environment to generate adequate responses for cell fitness and survival. Recent microscopy experiments have been able to monitor transcription from single genes in individual cells. These observations have revealed two striking features: transcriptional activity can vary markedly from one cell to another, and is subject to large changes over time, sometimes within minutes. How the chromatin structure, transcription machinery assembly and signalling networks generate such patterns is still unclear. In this review, we present the techniques used to investigate transcription from single genes, introduce quantitative modelling tools, and discuss transcription mechanisms and their implications for gene expression regulation.
| S-EPMC3321162 | biostudies-other
Project description:Laboratory cultivation of viruses is critical for determining requirements for viral replication, developing detection methods, identifying drug targets, and developing antivirals. Several viruses have a history of recalcitrance towards robust replication in laboratory cell lines, including human noroviruses and hepatitis B and C viruses. These viruses have tropism for tissue components of the enterohepatic circulation system: the intestine and liver, respectively. The purpose of this review is to discuss how key enterohepatic signaling molecules, bile acids (BAs), and BA receptors are involved in the replication of these viruses and how manipulation of these factors was useful in the development and/or optimization of culture systems for these viruses. BAs have replication-promoting activities through several key mechanisms: (1) affecting cellular uptake, membrane lipid composition, and endocytic acidification; (2) directly interacting with viral capsids to influence binding to cells; and (3) modulating the innate immune response. Additionally, expression of the Na+-taurocholate cotransporting polypeptide BA receptor in continuous liver cell lines is critical for hepatitis B virus entry and robust replication in laboratory culture. Viruses are capable of hijacking normal cellular functions, and understanding the role of BAs and BA receptors, components of the enterohepatic system, is valuable for expanding our knowledge on the mechanisms of norovirus and hepatitis B and C virus replication.
| S-EPMC8227374 | biostudies-literature
Project description:Positive transcription elongation factor b (P-TEFb), which comprises cyclin-dependent kinase 9 (CDK9) kinase and cyclin T subunits, is an essential kinase complex in human cells. Phosphorylation of the negative elongation factors by P-TEFb is required for productive elongation of transcription of protein-coding genes by RNA polymerase II (pol II). In addition, P-TEFb-mediated phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of pol II mediates the recruitment of transcription and RNA processing factors during the transcription cycle. CDK9 also phosphorylates p53, a tumor suppressor that plays a central role in cellular responses to a range of stress factors. Many viral factors affect transcription by recruiting or modulating the activity of CDK9. In this review, we will focus on how the function of CDK9 is regulated by viral gene products. The central role of CDK9 in viral life cycles suggests that drugs targeting the interaction between viral products and P-TEFb could be effective anti-viral agents.
| S-EPMC4863834 | biostudies-literature
Project description:MOTIVATION:The use of experimental information has been demonstrated to increase the success rate of computational macromolecular docking. Many methods use information to post-filter the simulation output while others drive the simulation based on experimental restraints, which can become problematic for more complex scenarios such as multiple binding interfaces. RESULTS:We present a novel method for including interface information into protein docking simulations within the LightDock framework. Prior to the simulation, irrelevant regions from the receptor are excluded for sampling (filter of initial swarms) and initial ligand poses are pre-oriented based on ligand input information. We demonstrate the applicability of this approach on the new 55 cases of the Protein-Protein Docking Benchmark 5, using different amounts of information. Even with incomplete or incorrect information, a significant improvement in performance is obtained compared to blind ab initio docking. AVAILABILITY AND IMPLEMENTATION:The software is supported and freely available from https://github.com/brianjimenez/lightdock and analysis data from https://github.com/brianjimenez/lightdock_bm5. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
| S-EPMC7005597 | biostudies-literature
Project description:BackgroundInsertion sequences (ISs) are small, mobile DNA entities able to expand in prokaryotic genomes and trigger important rearrangements. To understand their role in evolution, accurate IS taxonomy is essential. The IS4 family is composed of approximately 70 elements and, like some other families, displays extremely elevated levels of internal divergence impeding its classification. The increasing availability of complete genome sequences provides a valuable source for the discovery of additional IS4 elements. In this study, this genomic database was used to update the structural and functional definition of the IS4 family.ResultsA total of 227 IS4-related sequences were collected among more than 500 sequenced bacterial and archaeal genomes, representing more than a three fold increase of the initial inventory. A clear division into seven coherent subgroups was discovered as well as three emerging families, which displayed distinct structural and functional properties. The IS4 family was sporadically present in 17 % of analyzed genomes, with most of them displaying single or a small number of IS4 elements. Significant expansions were detected only in some pathogens as well as among certain extremophiles, suggesting the probable involvement of some elements in bacterial and archaeal adaptation and/or evolution. Finally, it should be noted that some IS4 subgroups and two emerging families occurred preferentially in specific phyla or exclusively inside a specific genus.ConclusionThe present taxonomic update of IS4 and emerging families will facilitate the classification of future elements as they arise from ongoing genome sequencing. Their narrow genomic impact and the existence of both IS-poor and IS-rich thriving prokaryotes suggested that these families, and probably ISs in general, are occasionally used as a tool for genome flexibility and evolution, rather than just representing self sustaining DNA entities.
| S-EPMC2266710 | biostudies-literature
Project description:Replication stress has emerged as a key driver of oncogenesis but also represents an Achilles' heel of cancer cells. Newly reported SUMO binding and SUMO ligase functions of the DNA repair protein SLX4 that influence the outcome of replication stress open new avenues for investigating the roles played by SLX4 in tumorigenesis.
| S-EPMC4905331 | biostudies-other