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Principle of marginotomy in the synthesis of polynucleotides at a template
... In 1965, Leonard Hayflick observed that primary human cells undergo only a finite number of cell divisions in culture, a phenomenon that was consequently termed the 'Hayflick limit' and is currently known as replicative senescence 4,5 . The Hayflick limit inspired Alexey Olovnikov to conceptualize the loss of telomeric material with each cell division 6,7 , which was coined the 'end-replication problem' by James Watson 8 . This theory was accompanied by premonitions of the role of telomere shortening in ageing and the presence of specialized enzymes in cancer and germ cells that elongate telomeres. ...
Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.
Changes in bone architecture and metabolism with aging increase the likelihood of osteoporosis and fracture. Age‐onset osteoporosis is multifactorial, with contributory extrinsic and intrinsic factors including certain medical problems, specific prescription drugs, estrogen loss, secondary hyperparathyroidism, microenvironmental and cellular alterations in bone tissue, and mechanical unloading or immobilization. At the histological level, there are changes in trabecular and cortical bone as well as marrow cellularity, lineage switching of mesenchymal stem cells to an adipogenic fate, inadequate transduction of signals during skeletal loading, and predisposition toward senescent cell accumulation with production of a senescence‐associated secretory phenotype. Cumulatively, these changes result in bone remodeling abnormalities that over time cause net bone loss typically seen in older adults. Age‐related osteoporosis is a geriatric syndrome due to the multiple etiologies that converge upon the skeleton to produce the ultimate phenotypic changes that manifest as bone fragility. Bone tissue is dynamic but with tendencies toward poor osteoblastic bone formation and relative osteoclastic bone resorption with aging. Interactions with other aging physiologic systems, such as muscle, may also confer detrimental effects on the aging skeleton. Conversely, individuals who maintain their BMD experience a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging. © 2023 American Physiological Society. Compr Physiol 13:4355‐4386, 2023.
Telomeres, essential for maintaining genomic stability, are typically preserved through the action of telomerase, a ribonucleoprotein complex that synthesizes telomeric DNA. One of its two core components, telomerase RNA (TR), serves as the template for this synthesis, and its evolution across different species is both complex and diverse. This review discusses recent advancements in understanding TR evolution, with a focus on plants (Viridiplantae). Utilizing novel bioinformatic tools and accumulating genomic and transcriptomic data, combined with corresponding experimental validation, researchers have begun to unravel the intricate pathways of TR evolution and telomere maintenance mechanisms. Contrary to previous beliefs, a monophyletic origin of TR has been demonstrated first in land plants and subsequently across the broader phylogenetic megagroup Diaphoretickes. Conversely, the discovery of plant-type TRs in insects challenges assumptions about the monophyletic origin of TRs in animals, suggesting evolutionary innovations coinciding with arthropod divergence. The review also highlights key challenges in TR identification and provides examples of how these have been addressed. Overall, this work underscores the importance of expanding beyond model organisms to comprehend the full complexity of telomerase evolution, with potential applications in agriculture and biotechnology.
Some tumors employ a mechanism called alternative lengthening of telomeres (ALT) to counteract telomere shortening‐induced replicative senescence. Several hallmarks are used to identify cell lines and tumors as ALT‐positive. Here, we analyzed a panel of ALT‐positive and ‐negative cancer cell lines to investigate the specificity and sensibility of ALT‐associated markers. We found that all the markers showed high sensitivity, indicating that cells not showing ALT markers are not ALT cells. Conversely, specificity varied significantly, i.e., many markers yield false positives. Detection of false positives may have influenced previous estimations of ALT incidence among tumors. Moreover, claims on the ‘coexistence’ of ALT and telomerase perhaps should be reconsidered. The findings prompt further study into the nature of these markers and their roles as either part of the ALT machinery or as by‐products.
Introduction . When a severe combined injury occurs in a patient, various biochemical, humoral, cellular and pathophysiological mechanisms of protection against death occur. Immediately after receiving an injury, the patient is hospitalized in a hospital for medical care, where every effort is made to stabilize the condition, resorting to the appointment of various instrumental and laboratory tests. The development and course of traumatic illness, and treatment outcomes in patients with similar injuries are sometimes dramatically different. Based on this, it was suggested that there is a genetic basis for the regularity of the disease, as well as that exogenous factors themselves can affect certain molecular genetic markers, primarily telomere length.
The objective was to summarize the current literature data on the study of changes in telomere length, as well as the influence of exogenous and endogenous factors on their shortening. To determine the prospects of studying the effect of polymorphic alleles of various genes on the development of a pathological condition in a certain cohort, namely the development of cognitive dysfunction in patients with severe trauma after repeated anesthesia.
Materials and methods. The literature search and analysis was performed in the medical information systems PubMed and eLibrary, using the keywords «telomere», «trauma», «cognitive», and «anesthesia».
Results . Since 1950, data on the study of human telomeres began to be published abroad. Between 2002 and the present, 39 articles were published on PubMed when searching for the keywords «anesthesia» and «telomeres»; by keywords «cognitive», «trauma», «telomeres» – 27. Most articles are devoted to the effect of childhood trauma on changes in telomere length, as well as the assessment of short telomeres in patients with various cognitive deficits. However, there are no articles devoted to studying the effect of repeated anesthesia, as an exogenous factor, on the genetic apparatus of a patient with severe combined trauma.
Conclusion . The literature highlights the influence of various exogenous factors on the shortening of telomere length, especially in the context of childhood trauma, cognitive impairment in various observed groups. The section related to the effects of anesthesia and their number, the consequences for the genetic apparatus of a particular person, is open for study.
Radiation cytogenetics has a rich history seldom appreciated by those outside the field. Early radiobiology was dominated by physics and biophysical concepts that borrowed heavily from the study of radiation-induced chromosome aberrations. From such studies, quantitative relationships between biological effect and changes in absorbed dose, dose rate and ionization density were codified into key concepts of radiobiological theory that have persisted for nearly a century. This review aims to provide a historical perspective of some of these concepts, including evidence supporting the contention that chromosome aberrations underlie development of many, if not most, of the biological effects of concern for humans exposed to ionizing radiations including cancer induction, on the one hand, and tumor eradication on the other. The significance of discoveries originating from these studies has widened and extended far beyond their original scope. Chromosome structural rearrangements viewed in mitotic cells were first attributed to the production of breaks by the radiations during interphase, followed by the rejoining or mis-rejoining among ends of other nearby breaks. These relatively modest beginnings eventually led to the discovery and characterization of DNA repair of double-strand breaks by non-homologous end joining, whose importance to various biological processes is now widely appreciated. Two examples, among many, are V(D)J recombination and speciation. Rapid technological advancements in cytogenetics, the burgeoning fields of molecular radiobiology and third-generation sequencing served as a point of confluence between the old and new. As a result, the emergent field of "cytogenomics" now becomes uniquely positioned for the purpose of more fully understanding mechanisms underlying the biological effects of ionizing radiation exposure.
Background
Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies.
Methods and results
Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients’ primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells.
Conclusion
These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.
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