scholarly journals Chromosome End Maintenance by Telomerase

2009 ◽  
Vol 284 (24) ◽  
pp. 16061-16065 ◽  
Author(s):  
Jennifer L. Osterhage ◽  
Katherine L. Friedman
Keyword(s):  
Genome Stability ◽  
Chromosomal Abnormalities ◽  
Human Aging ◽  
Dna Complexes ◽  
Telomeric Sequences ◽  
Telomere Elongation ◽  
Telomere Function ◽  
Multiple Levels ◽  
Linear Chromosomes

Telomeres, protein-DNA complexes at the ends of eukaryotic linear chromosomes, are essential for genome stability. The accumulation of chromosomal abnormalities in the absence of proper telomere function is implicated in human aging and cancer. Repetitive telomeric sequences are maintained by telomerase, a ribonucleoprotein complex containing a reverse transcriptase subunit, a template RNA, and accessory components. Telomere elongation is regulated at multiple levels, including assembly of the telomerase holoenzyme, recruitment of telomerase to the chromosome terminus, and telomere accessibility. This minireview provides an overview of telomerase structure, function, and regulation and the role of telomerase in human disease.

scholarly journals Telomeric and Sub-Telomeric Structure and Implications in Fungal Opportunistic Pathogens

2021 ◽  
Vol 9 (7) ◽  
pp. 1405
Author(s):  
Raffaella Diotti ◽  
Michelle Esposito ◽  
Chang Hui Shen
Keyword(s):  
Fungal Pathogens ◽  
Functional Abilities ◽  
Opportunistic Pathogens ◽  
Telomeric Sequences ◽  
Coding Regions ◽  
Telomeric Structure ◽  
Linear Chromosomes ◽  
Dna Ends ◽  
Telomere Structure

Telomeres are long non-coding regions found at the ends of eukaryotic linear chromosomes. Although they have traditionally been associated with the protection of linear DNA ends to avoid gene losses during each round of DNA replication, recent studies have demonstrated that the role of these sequences and their adjacent regions go beyond just protecting chromosomal ends. Regions nearby to telomeric sequences have now been identified as having increased variability in the form of duplications and rearrangements that result in new functional abilities and biodiversity. Furthermore, unique fungal telomeric and chromatin structures have now extended clinical capabilities and understanding of pathogenicity levels. In this review, telomere structure, as well as functional implications, will be examined in opportunistic fungal pathogens, including Aspergillus fumigatus, Candida albicans, Candida glabrata, and Pneumocystis jirovecii.

scholarly journals Inflammation increases cells expressing ZSCAN4 and progenitor cell markers in the adult pancreas

2013 ◽  
Vol 304 (12) ◽  
pp. G1103-G1116 ◽  
Author(s):  
Shigeru B. H. Ko ◽  
Sakiko Azuma ◽  
Yukihiro Yokoyama ◽  
Akiko Yamamoto ◽  
Kazuhiro Kyokane ◽  
...  
Keyword(s):  
Autoimmune Pancreatitis ◽  
Genome Stability ◽  
Progenitor Cell ◽  
Es Cells ◽  
Embryonic Stem ◽  
Corticosteroid Treatment ◽  
Human Pancreas ◽  
Cell Markers ◽  
Telomere Elongation

We have recently identified the zinc finger and SCAN domain containing 4 (Zscan4), which is transiently expressed and regulates telomere elongation and genome stability in mouse embryonic stem (ES) cells. The aim of this study was to examine the expression of ZSCAN4 in the adult pancreas and elucidate the role of ZSCAN4 in tissue inflammation and subsequent regeneration. The expression of ZSCAN4 and other progenitor or differentiated cell markers in the human pancreas was immunohistochemically examined. Pancreas sections of alcoholic or autoimmune pancreatitis patients before and under maintenance corticosteroid treatment were used in this study. In the adult human pancreas a small number of ZSCAN4-positive (ZSCAN4+) cells are present among cells located in the islets of Langerhans, acini, ducts, and oval-shaped cells. These cells not only express differentiated cell markers for each compartment of the pancreas but also express other tissue stem/progenitor cell markers. Furthermore, the number of ZSCAN4+cells dramatically increased in patients with chronic pancreatitis, especially in the pancreatic tissues of autoimmune pancreatitis actively regenerating under corticosteroid treatment. Interestingly, a number of ZSCAN4+cells in the pancreas of autoimmune pancreatitis returned to the basal level after 1 yr of maintenance corticosteroid treatment. In conclusion, coexpression of progenitor cell markers and differentiated cell markers with ZSCAN4 in each compartment of the pancreas may indicate the presence of facultative progenitors for both exocrine and endocrine cells in the adult pancreas.

scholarly journals Ku80 is involved in telomere maintenance but dispensable for genomic stability in Leishmania mexicana

2021 ◽  
Vol 15 (12) ◽  
pp. e0010041
Author(s):  
Ester Poláková ◽  
Amanda T. S. Albanaz ◽  
Alexandra Zakharova ◽  
Tatiana S. Novozhilova ◽  
Evgeny S. Gerasimov ◽  
...  
Keyword(s):  
Genome Stability ◽  
Southern Blotting ◽  
Telomere Maintenance ◽  
Genome Integrity ◽  
Whole Genome ◽  
Leishmania Mexicana ◽  
Telomere Elongation ◽  
Ku Proteins ◽  
Telomere Lengthening

Background Telomeres are indispensable for genome stability maintenance. They are maintained by the telomere-associated protein complex, which include Ku proteins and a telomerase among others. Here, we investigated a role of Ku80 in Leishmania mexicana. Leishmania is a genus of parasitic protists of the family Trypanosomatidae causing a vector-born disease called leishmaniasis. Methodology/Principal findings We used the previously established CRISPR/Cas9 system to mediate ablation of Ku80- and Ku70-encoding genes in L. mexicana. Complete knock-outs of both genes were confirmed by Southern blotting, whole-genome Illumina sequencing, and RT-qPCR. Resulting telomeric phenotypes were subsequently investigated using Southern blotting detection of terminal restriction fragments. The genome integrity in the Ku80- deficient cells was further investigated by whole-genome sequencing. Our work revealed that telomeres in the ΔKu80 L. mexicana are elongated compared to those of the wild type. This is a surprising finding considering that in another model trypanosomatid, Trypanosoma brucei, they are shortened upon ablation of the same gene. A telomere elongation phenotype has been documented in other species and associated with a presence of telomerase-independent alternative telomere lengthening pathway. Our results also showed that Ku80 appears to be not involved in genome stability maintenance in L. mexicana. Conclusion/Significance Ablation of the Ku proteins in L. mexicana triggers telomere elongation, but does not have an adverse impact on genome integrity.

scholarly journals Genome stability is guarded by yeast Rtt105 through multiple mechanisms

Genetics ◽  
2021 ◽  
Vol 217 (2) ◽  
Author(s):  
Yves Corda ◽  
Laetitia Maestroni ◽  
Pierre Luciano ◽  
Maria Y Najem ◽  
Vincent Géli
Keyword(s):  
Genome Stability ◽  
Large Subunit ◽  
Telomere Maintenance ◽  
Mobile Dna ◽  
Yeast Saccharomyces Cerevisiae ◽  
Genetic Analyses ◽  
Telomere Elongation ◽  
Defects Analysis ◽  
In Cells

Abstract Ty1 mobile DNA element is the most abundant and mutagenic retrotransposon present in the genome of the budding yeast Saccharomyces cerevisiae. Protein regulator of Ty1 transposition 105 (Rtt105) associates with large subunit of RPA and facilitates its loading onto a single-stranded DNA at replication forks. Here, we dissect the role of RTT105 in the maintenance of genome stability under normal conditions and upon various replication stresses through multiple genetic analyses. RTT105 is essential for viability in cells experiencing replication problems and in cells lacking functional S-phase checkpoints and DNA repair pathways involving homologous recombination. Our genetic analyses also indicate that RTT105 is crucial when cohesion is affected and is required for the establishment of normal heterochromatic structures. Moreover, RTT105 plays a role in telomere maintenance as its function is important for the telomere elongation phenotype resulting from the Est1 tethering to telomeres. Genetic analyses indicate that rtt105Δ affects the growth of several rfa1 mutants but does not aggravate their telomere length defects. Analysis of the phenotypes of rtt105Δ cells expressing NLS-Rfa1 fusion protein reveals that RTT105 safeguards genome stability through its role in RPA nuclear import but also by directly affecting RPA function in genome stability maintenance during replication.

scholarly journals Either Rap1 or Cdc13 can protect telomeric single-stranded 3′ overhangs from degradation in vitro

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rikard Runnberg ◽  
Saishyam Narayanan ◽  
Humberto Itriago ◽  
Marita Cohn
Keyword(s):  
Genome Stability ◽  
Replicative Senescence ◽  
Repetitive Sequences ◽  
Protein Structures ◽  
Telomeric Dna ◽  
Telomere Function ◽  
Exonucleolytic Degradation ◽  
Linear Chromosomes ◽  
Insight Into

AbstractTelomeres, the DNA-protein structures capping the ends of linear chromosomes, are important for regulating replicative senescence and maintaining genome stability. Telomeres consist of G-rich repetitive sequences that end in a G-rich single-stranded (ss) 3′ overhang, which is vital for telomere function. It is largely unknown how the 3′ overhang is protected against exonucleases. In budding yeast, double-stranded (ds) telomeric DNA is bound by Rap1, while ssDNA is bound by Cdc13. Here, we developed an in vitro DNA 3′end protection assay to gain mechanistic insight into how Naumovozyma castellii Cdc13 and Rap1 may protect against 3′ exonucleolytic degradation by Exonuclease T. Our results show that Cdc13 protects the 3′ overhang at least 5 nucleotides (nt) beyond its binding site, when bound directly adjacent to the ds-ss junction. Rap1 protects 1–2 nt of the 3′ overhang when bound to dsDNA adjacent to the ds-ss junction. Remarkably, when Rap1 is bound across the ds-ss junction, the protection of the 3′ overhang is extended to 6 nt. This shows that binding by either Cdc13 or Rap1 can protect telomeric overhangs from 3′ exonucleolytic degradation, and suggests a new important role for Rap1 in protecting short overhangs under circumstances when Cdc13 cannot bind the telomere.

scholarly journals Key role of piRNAs in telomeric chromatin maintenance and telomere nuclear positioning in Drosophila germline

2017 ◽  
Author(s):  
Elizaveta Radion ◽  
Valeriya Morgunova ◽  
Sergei Ryazansky ◽  
Natalia Akulenko ◽  
Sergey Lavrov ◽  
...  
Keyword(s):  
Small Rnas ◽  
Telomere Dysfunction ◽  
Specific Mechanism ◽  
Telomere Elongation ◽  
Histone 3 ◽  
Telomere Function ◽  
Telomere Homeostasis ◽  
End Capping ◽  
Pirna Pathway

AbstractTelomeric small RNAs related to PIWI-interacting RNAs (piRNAs) were discovered in different species, however, their role in germline-specific telomere function remains poorly understood. Using a Drosophila model, we show that the piRNA pathway provides a strong germline-specific mechanism of telomere homeostasis. We show that telomeric retrotransposon arrays belong to a unique class of dual-strand piRNA clusters whose transcripts, required for telomere elongation, serve simultaneously as piRNA precursors and their only targets. However, the ability to produce piRNAs and bind Rhino – a germline-specific homolog of heterochromatic protein 1 (HP1) – varies along telomeres. Most likely, this heterogeneity is determined by the peculiarities of telomeric retrotransposons themselves. piRNAs play a pivotal role in the establishment and maintenance of telomeric and subtelomeric chromatin in the germline facilitating loading of HP1 and histone 3 lysine 9 trimethylation mark – highly conservative telomere components – at different telomeric regions. piRNA pathway disruption results in telomere dysfunction characterized by a loss of heterochromatic components and translocation of telomeres from the periphery to the nuclear interior but does not affect the telomere end capping.

The Role of For-Profit Firms in Disaster Management: A Typology

2021 ◽  
pp. 027614672110201
Author(s):  
Swapan Deep Arora ◽  
Anirban Chakraborty
Keyword(s):  
Disaster Management ◽  
Community Resilience ◽  
Sustained Development ◽  
For Profit ◽  
State Initiative ◽  
Marketing Orientation ◽  
Disaster Studies ◽  
Building Community ◽  
Multiple Levels

Contemporary existence presents a duality of sustained development and recurrent disasters. Whereas disaster studies have closely examined public policy and state initiative, the role of for-profits is under-explored. Stakeholder theory and its integration with marketing orientation provide a theoretical underpinning for understanding the behavior of firms across contingencies, including disasters. Accordingly, we traverse the range of actions that these market entities exhibit in aiding disaster management and develop a comprehensive typology. The current COVID-19 pandemic provides a context for illustrating the practical exemplar actions as mapped to the proposed typology. We add to theory by examining the role of marketing philosophy and for-profits in tackling disasters at multiple levels: from micro-aspects of maintaining relations with specific stakeholders to the macro-objective of building community resilience. Further, the proposed typology helps practice and research by highlighting the range of firms' responses contributing to disaster management and building community resilience.

scholarly journals Connecting the αα-hubs: same fold, disordered ligands, new functions

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lasse Staby ◽  
Katrine Bugge ◽  
Rasmus Greve Falbe-Hansen ◽  
Edoardo Salladini ◽  
Karen Skriver ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Telomere Elongation ◽  
Protein Protein Interaction ◽  
Intrinsically Disordered ◽  
Functional Understanding ◽  
Signal Specificity ◽  
Telomere Regulation ◽  
Secondary Structure Motif

Abstract Background Signal fidelity depends on protein–protein interaction–‘hubs’ integrating cues from large interactomes. Recently, and based on a common secondary structure motif, the αα-hubs were defined, which are small α-helical domains of large, modular proteins binding intrinsically disordered transcriptional regulators. Methods Comparative structural biology. Results We assign the harmonin-homology-domain (HHD, also named the harmonin N-terminal domain, NTD) present in large proteins such as harmonin, whirlin, cerebral cavernous malformation 2, and regulator of telomere elongation 1 to the αα-hubs. The new member of the αα-hubs expands functionality to include scaffolding of supra-modular complexes mediating sensory perception, neurovascular integrity and telomere regulation, and reveal novel features of the αα-hubs. As a common trait, the αα-hubs bind intrinsically disordered ligands of similar properties integrating similar cellular cues, but without cross-talk. Conclusion The inclusion of the HHD in the αα-hubs has uncovered new features, exemplifying the utility of identifying groups of hub domains, whereby discoveries in one member may cross-fertilize discoveries in others. These features make the αα-hubs unique models for decomposing signal specificity and fidelity. Using these as models, together with other suitable hub domain, we may advance the functional understanding of hub proteins and their role in cellular communication and signaling, as well as the role of intrinsically disordered proteins in signaling networks.

scholarly journals Targeting Hedgehog Signalling through the Ubiquitylation Process: The Multiple Roles of the HECT-E3 Ligase Itch

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 98 ◽  
Author(s):  
Paola Infante ◽  
Ludovica Lospinoso Severini ◽  
Flavia Bernardi ◽  
Francesca Bufalieri ◽  
Lucia Di Marcotullio
Keyword(s):  
E3 Ligase ◽  
Multiple Roles ◽  
Post Translational Modification ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Promising Target ◽  
Important Pathway ◽  
Multiple Levels

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.

scholarly journals Telomerase RNA Template Mutations Reveal Sequence-Specific Requirements for the Activation and Repression of Telomerase Action at Telomeres

2000 ◽  
Vol 20 (8) ◽  
pp. 2941-2948 ◽  
Author(s):  
John C. Prescott ◽  
Elizabeth H. Blackburn
Keyword(s):  
Enzymatic Activity ◽  
Activity Levels ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Telomere Elongation ◽  
Telomere Binding Protein ◽  
Telomere Function ◽  
Double Base ◽  
Telomere Lengthening

ABSTRACT Telomeric DNA is maintained within a length range characteristic of an organism or cell type. Significant deviations outside this range are associated with altered telomere function. The yeast telomere-binding protein Rap1p negatively regulates telomere length. Telomere elongation is responsive to both the number of Rap1p molecules bound to a telomere and the Rap1p-centered DNA-protein complex at the extreme telomeric end. Previously, we showed that a specific trinucleotide substitution in the Saccharomyces cerevisiae telomerase gene (TLC1) RNA template abolished the enzymatic activity of telomerase, causing the same cell senescence and telomere shortening phenotypes as a complete tlc1 deletion. Here we analyze effects of six single- and double-base changes within these same three positions. All six mutant telomerases had in vitro enzymatic activity levels similar to the wild-type levels. The base changes predicted from the mutations all disrupted Rap1p binding in vitro to the corresponding duplex DNAs. However, they caused two classes of effects on telomere homeostasis: (i) rapid, RAD52-independent telomere lengthening and poor length regulation, whose severity correlated with the decrease in in vitro Rap1p binding affinity (this is consistent with loss of negative regulation of telomerase action at these telomeres; and (ii) telomere shortening that, depending on the template mutation, either established a new short telomere set length with normal cell growth or was progressive and led to cellular senescence. Hence, disrupting Rap1p binding at the telomeric terminus is not sufficient to deregulate telomere elongation. This provides further evidence that both positive and negativecis-acting regulators of telomerase act at telomeres.

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