Targeting Telomerase

Siddiqa, Aisha; Cavazos, David; Marciniak, Robert A.

doi:10.1089/rej.2006.9.378

Cited by 19 publications

(5 citation statements)

References 73 publications

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“…A study by Reddel and colleagues [101] identifies a correlation between patient age and ALT activation, which is seen mostly in young individuals [101]. Furthermore, it has also been discussed that treatment of telomerase-positive tumors with telomerase inhibitors may select for cells which activate ALT [104, 105]. Thus, fully understanding the role of BLM and its modification on APB formation and telomere recombination could potentially provide novel therapeutic targets, particularly because significant progress has been made in developing small molecule inhibitors of BLM [106].…”

Section: Discussionmentioning

confidence: 99%

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Böhm

Bernstein

2014

DNA Repair

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RecQ-like helicases are a highly conserved family of proteins which are critical for preserving genome integrity. Genome instability is considered a hallmark of cancer and mutations within three of the five human RECQ genes cause hereditary syndromes that are associated with cancer predisposition. The human RecQ-like helicase BLM has a central role in DNA damage signaling, repair, replication, and telomere maintenance. BLM and its budding yeast orthologue Sgs1 unwind double-stranded DNA intermediates. Intriguingly, BLM functions in both a pro- and anti-recombinogenic manner upon replicative damage, acting on similar substrates. Thus, BLM activity must be intricately controlled to prevent illegitimate recombination events that could have detrimental effects on genome integrity. In recent years it has become evident that post-translational modifications (PTMs) of BLM allow a fine-tuning of its function. To date, BLM phosphorylation, ubiquitination, and SUMOylation have been identified, in turn regulating its subcellular localization, protein-protein interactions, and protein stability. In this review, we will discuss the cellular context of when and how these different modifications of BLM occur. We will reflect on the current model of how PTMs control BLM function during DNA damage repair and compare this to what is known about post-translational regulation of the budding yeast orthologue Sgs1. Finally, we will provide an outlook towards future research, in particular to dissect the cross-talk between the individual PTMs on BLM.

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Section: Discussionmentioning

confidence: 99%

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

Böhm

Bernstein

2014

DNA Repair

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“…Cells of the germ line, stem cells and some other normal diploid cells contain an enzyme called telomerase that replaces telomer DNA lost during cell division. The possibility of reversing cellular senescence by switching on a copy of the gene encoding the telomerase catalytic subunit into normal cells, thus turning on telomerase activity has been considered [24][25][26][27][28][29][30][31][32][33][34][35]. This strategy may also increase the risk that cells become immortalized.…”

Section: Cellular Senescence and Telomeresmentioning

confidence: 99%

A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part I: Cellular and molecular perspectives of skin ageing

Callaghan¹,

Wilhelm

2008

Intern J of Cosmetic Sci

133

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The ageing process is noticeable within all organs of the body and manifests itself visibly in the skin. Skin ageing is influenced by several factors including genetics, environmental exposure, hormonal changes and metabolic processes. Together these factors lead to cumulative alterations of skin structure, function and appearance. The functioning of the central nervous, immune, endocrine and cardiovascular systems, as well as the skin is also impaired with age. Chronologically, aged skin is thin, relatively flattened, dry and unblemished, with some loss of elasticity and age-related loss of architectural regularity. General atrophy of the extracellular matrix is reflected by a decrease in the number of fibroblasts. Reduced levels of collagen and elastin, with impaired organization are primarily because of decreased protein synthesis affecting types I and III collagen in the dermis, with an increased breakdown of extracellular matrix proteins. Oxidative stress is considered of primary importance in driving the ageing process. The original free radical theory of ageing purported that the molecular basis of ageing was derived from a lifetime accumulation of oxidative damage to cells resulting from excess reactive oxygen species (ROS) produced as a consequence of aerobic metabolism. Although the skin possesses extremely efficient anti-oxidant activities, during ageing, ROS levels rise and anti-oxidant activities decline. The ROS are necessary in multiple MAP kinase pathways and the induction of AP-1, in turn, up-regulates expression of matrix-metalloproteinases providing a plausible mechanism for the increased collagen degradation in aged human skin. Ré suméLe processus de vieillissement est perceptible sur tous les organes du corps et se manifeste clairement au niveau de la peau. Le vieillissement de la peau est influencée par plusieurs facteurs comme la génétique, l'exposition environnementale, les variations hormonales, les mécanismes métaboli-ques. Ensemble, ces différents facteurs conduisent à des altérations cumulatives de la structure de la peau, de sa fonction et de son apparence. Le fonctionnement du système nerveux central, immunitaire, endocrinien et cardio-vasculaire est, comme la peau, touché par l'âge. La peau âgée est fine, relativement relâchée, sèche et sans défaut avec

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“…Never-theless, anti-telomerase therapies are obviously of no value in telomerase non-expressing tumours, not to mention potential toxicity due to off-target effects. Furthermore, anti-telomerase treatment can always drive to selection for resistant cells that may activate an ALT mechanism [167]. These data render ALT an attractive target for anti-tumour therapies based on a personalized treatment approach.…”

Section: Alt-mediated Telomere Elongationmentioning

confidence: 99%

DNA Repair and Telomeres — An Intriguing Relationship

Boutou¹,

Vlachodimitropoulos²,

Pappa³

et al. 2013

New Research Directions in DNA Repair

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ment of telomere integrity accompanied by cellular checkpoints abrogation. Quite interestingly, it seems that the pleiotropic effects governing a cell's decision to senesce vs. undergoing apoptosis when reaching the so-called Hayflick limit [9] (certain number of cell divisions), comprise a fertile environment for cancer formation. Cancer cells have developed numerous strategies towards bypassing these limits on the road to achieving eternal proliferation. Genomic stability and telomeresGenomic stability is the prerequisite of species survival as ensures that all required information will be passed on to the next generations. In contrast to single-cell -quickly dividing -species, higher order organisms, in order to preserve their genomic information, require more efficient DNA repair mechanisms due to later onset of reproduction. Therefore, a remarkable ability of cells to recognize and repair DNA damage and progress through the cell cycle, in a regulated and orderly manner, has been developed. A vulnerable portion of the genome, especially in eukaryotic organisms whose genome is organised in linear chromosomes, is their edges called telomeres (after the greek words 'τέλος' (télos) and 'μέρος' (méros) meaning 'the ending part'). Telomeres are nucleoprotein complexes that 'cap' the chromosomes' physical ends. In most eukaryotic organisms integral and stable telomeres guarantee the maintenance of genetic information and its accurate transfer to the next generation. In case telomeres are impaired, abnormal ends are recognised by the DNA damage detection machinery as double-strand DNA (dsDNA) breaks, the DDR is activated and the lesion is healed by Non-Homologous-End-Joining (NHEJ) repair activities. The result of this type of repair may be the fusion of chromosomes and the formation of dicentric /polycentric chromosomes leading in turn to further genomic instability. For this reason a number of telomere-binding protein complexes are associated with telomeres to ensure the formation of a proper secondary structure and a capping function. Intriguingly, a number of protein complexes implicated in DNA repair also contribute to telomere stability. The structure of telomeres is intrinsically dynamic, as chromosome ends should relax during genome replication and then re-establish their 'capped' state after replication. Consequently, telomeres may switch between closed (protected) and open (replication-competent) states during the cell cycle. Each state is governed by a number of interactions with specific factors and can lead the cell to either cell division or senescence / apoptosis under normal conditions, or to disorders / cancer in abnormal cases (processes still poorly understood in a large extent) [10][11]. Moreover, during development and in certain cell types in adults, telomere length should be preserved. Thus, multiple physiological processes guarantee functional and structural heterogeneity of telomeres concerning their length and nucleoprotein composition. A functional chromosome end structure is essential for ...

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Targeting Telomerase

Cited by 19 publications

References 73 publications

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

The role of post-translational modifications in fine-tuning BLM helicase function during DNA repair

A review of ageing and an examination of clinical methods in the assessment of ageing skin. Part I: Cellular and molecular perspectives of skin ageing

DNA Repair and Telomeres — An Intriguing Relationship

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