scholarly journals Telomere Targeting Approaches in Cancer: Over the Length Maintenance.

2021 ◽  
Author(s):  
Eleonora Vertecchi ◽  
Angela Rizzo ◽  
Erica Salvati
Keyword(s):  
Genome Stability ◽  
Telomere Maintenance ◽  
Cancer Drug ◽  
Signalling Pathways ◽  
Telomere Elongation ◽  
Intracellular Signalling Pathways ◽  
Anti Cancer ◽  
Cancer Cell Survival ◽  
Dna Damage Signalling ◽  
Telomere Length Homeostasis

Telomeres are crucial structures that preserve genome stability. Their progressive erosion over rounds of DNA duplication determines senescence of cells and organisms. Telomere length homeostasis is critical for cancer development then telomere maintenance mechanisms are established targets in cancer treatment. Besides telomere elongation, telomere’s dysfunction impinges on intracellular signalling pathways, in particular DNA damage signalling and repair affecting cancer cell survival and proliferation. This review summarizes and discusses about the recent findings in anti-cancer drug development targeting different “telosome” components.

Editorial (Thematic Issue: Signalling Pathways in Anti-cancer Drug Resistance)

2014 ◽  
Vol 21 (26) ◽  
pp. 3007-3008 ◽  
Author(s):  
Chen Chen ◽  
Jiezhong Chen ◽  
Kong-Nan Zhao
Keyword(s):  
Drug Resistance ◽  
Thematic Issue ◽  
Cancer Drug ◽  
Signalling Pathways ◽  
Cancer Drug Resistance ◽  
Anti Cancer

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 HeterozygousRTEL1mutations are associated with familial pulmonary fibrosis

2015 ◽  
Vol 46 (2) ◽  
pp. 474-485 ◽  
Author(s):  
Caroline Kannengiesser ◽  
Raphael Borie ◽  
Christelle Ménard ◽  
Marion Réocreux ◽  
Patrick Nitschké ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Genome Stability ◽  
Dna Helicase ◽  
Telomere Maintenance ◽  
Candidate Gene Approach ◽  
Autosomal Dominant Trait ◽  
Telomere Shortening ◽  
Telomere Elongation ◽  
Whole Exome ◽  
Familial Pulmonary Fibrosis

Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genesTERT(reverse transcriptase) andTERC(RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised.Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF withoutTERTandTERCmutations.We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygousRTEL1mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this,RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls.Our results provide evidence that heterozygousRTEL1mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus,RTEL1enlarges the number of telomere-associated genes implicated in FPF.

Therapeutic potential of natural compounds in lung cancer

2021 ◽  
Vol 28 ◽  
Author(s):  
Minnatallah Al-Yozbaki ◽  
Peter J. Wilkin ◽  
Girish Kumar Gupta ◽  
Cornelia M. Wilson
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Natural Compound ◽  
Cell Signalling ◽  
Natural Compounds ◽  
Cancer Drug ◽  
Signalling Pathways ◽  
Cancer Drugs ◽  
Anti Cancer

: Lung cancer is a leading cause of cancer deaths worldwide. The management of lung cancer treatment is often ineffective as a result of the development of drug resistance, reactions to treatment, drug-drug interactions or non-specific targeting of the anti-cancer drugs. Natural compounds show promise and potential activity in lung cancer with very few side effects. While, the combinatorial action of an anti-cancer drug with a natural compound provide synergistic action which help to boost the overall therapeutic action against cancer cells. In cancer, there is a dysregulation of apoptosis which facilitates the cancer cell to survive resulting in progression of the cancer. Many cancer drugs cause mutations of genes that regulate the cancer which should kill the cancer cell but lead to chemoresistance. There are many natural compounds that could specifically target different cell signalling pathways associated with cancer progression to provide a cytotoxic effect in the target cell. The importance of these compounds is emerging in many therapies developed with dual action often including a natural compound. In this review, we present a selection of these natural compounds and how they target lung cancer cells with a focus on the cell signalling pathways. Further work is required to delineate the potential action of natural compounds in the treatment against cancer.

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 KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity

2019 ◽  
Author(s):  
Marjorie Fournier ◽  
Jean-Yves Bleuyard ◽  
Anthony M. Couturier ◽  
Jessica Ellins ◽  
Svenja Hester ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcriptional Activation ◽  
Genome Stability ◽  
Specific Binding ◽  
Genotoxic Stress ◽  
Cancer Drug ◽  
Dna Breaks ◽  
Naked Dna ◽  
Anti Cancer ◽  
Lysine Residues

SummaryThe tumour suppressor PALB2 stimulates error-free repair of DNA breaks, whilst its steady-state chromatin association protects active genes from genotoxic stress. Here, we report that the lysine acetyltransferases 2A and 2B (KAT2A/B), commonly known to promote transcriptional activation, acetylate the PALB2 chromatin association motif (ChAM), providing a dynamic regulatory mechanism for PALB2. ChAM acetylation within a cluster of seven lysine residues (7K), detected in the chromatin-enriched fraction in undamaged cells, enhanced its association with nucleosomes while decreasing its non-specific binding to naked DNA. DNA damage triggered a rapid deacetylation of ChAM and a concomitant increase in PALB2 mobility. Significantly, a 7K-null mutation, which hindered ChAM binding to both nucleosomes and DNA, conferred deficiency in DNA repair and hypersensitivity to the anti-cancer drug olaparib. Thus, our study reveals a unique mechanism mediated by KAT2A/B-dependent acetylation of a non-histone protein, which fine-tunes the DNA damage response and hence promotes genome stability.

Caspases and apoptosis

2002 ◽  
Vol 38 ◽  
pp. 9-19 ◽  
Author(s):  
Guy S Salvesen
Keyword(s):  
Cysteine Proteases ◽  
Signalling Pathways ◽  
Term Survival ◽  
Mature Adult ◽  
Intracellular Signalling Pathways ◽  
Adult Cell ◽  
Caspase Family ◽  
Cell Fragments ◽  
Pro Inflammatory Cytokines

The ability of metazoan cells to undergo programmed cell death is vital to both the precise development and long-term survival of the mature adult. Cell deaths that result from engagement of this programme end in apoptosis, the ordered dismantling of the cell that results in its 'silent' demise, in which packaged cell fragments are removed by phagocytosis. This co-ordinated demise is mediated by members of a family of cysteine proteases known as caspases, whose activation follows characteristic apoptotic stimuli, and whose substrates include many proteins, the limited cleavage of which causes the characteristic morphology of apoptosis. In vertebrates, a subset of caspases has evolved to participate in the activation of pro-inflammatory cytokines, and thus members of the caspase family participate in one of two very distinct intracellular signalling pathways.

Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes

Xenobiotica ◽  
2009 ◽  
Vol 00 (00) ◽  
pp. 090901052053001-8
Author(s):  
K. Murai ◽  
H. Yamazaki ◽  
K. Nakagawa ◽  
R. Kawai ◽  
T. Kamataki
Keyword(s):  
Cytochrome P450 ◽  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Cancer Drug ◽  
Anti Cancer ◽  
Cytochrome P450 2A6
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