Importancia biológica de los telómeros / Biological importance of telomeres

Se exponen los hallazgos históricos y la importancia biológica de los telómeros en la vida celular y en los aspectos genéticos del ADN humano. (AU)

The discovery and the biological importance of the telomeres are exposed. (AU)

Oxidative stress, telomere length, and frailty in an old age population

Abstract Background A global aging population requires focusing on the risk factors for unhealthy aging, preventive medicine, and chronic disease management. The identification of adverse health outcomes in older adults has been addressed by the characterization of frailty as a biological syndrome. In this field, oxidative stress and telomere length have been suggested as biomarkers of aging Objective The objective of the study was to study the association of oxidative stress, telomere length, and frailty in an old age population Methods We conducted a cross-sectional study based on 2015 data from 202 members of a cohort of older adults (n = 202; F/M gender ratio: 133/69; mean age: 69.89 ± 7.39 years). Reactive oxygen species were measured by dichlorofluorescein diacetate and lipid peroxidation by malondialdehyde. Telomere length was determined using quantitative polymerase chain reaction with SYBR Green Master Mix Results Statistical analysis showed an association between telomere length and frailty but no association between oxidative stress and telomere length or frailty Conclusions Telomere length could eventually be used as a marker to differentiate between healthy and unhealthy aging as expressed by frailty phenotype; oxidative stress seemed merely a biological process of aging.

Synaptic configuration of quadrivalents and their association with the XY bivalent in spermatocytes of Robertsonian heterozygotes of Mus domesticus

BACKGROUND: The nuclear architecture of meiotic prophase spermatocytes is based on higher-order patterns of spatial associations among chromosomal domains and consequently is prone to modification by chromosomal rearrangements. We have shown that nuclear architecture is modified in spermatocytes of Robertsonian (Rb) homozygotes of Mus domesticus. In this study we analyse the synaptic configuration of the quadrivalents formed in the meiotic pro- phase of spermatocytes of mice double heterozygotes for the dependent Rb chromosomes: Rbs 11.16 and 16.17. RESULTS: Electron microscope spreads of 60 pachytene spermatocytes from four animals of Mus domesticus 2n = 38 were studied and their respective quadrivalents analysed in detail. Normal synaptonemal complex was found between arms 16 of the Rb metacentric chromosomes, telocentrics 11 and 17 and homologous arms of the Rb metacentric chromosomes. About 43% of the quadrivalents formed a synaptonemal complex between the heterologous short arms of chromosomes 11 and 17. This synaptonemal complex is bound to the nuclear envelope through a fourth synapsed telomere, thus dragging the entire quadrivalent to the nuclear envelope. About 57% of quadrivalents showed unsynapsed single axes in the short arms of the telocentric chromosomes. About 90% of these unsynapsed quadrivalents also showed a telomere-to-telomere association between one of the single axes of the telocentric chromosome 11 or 17 and the X chromosome single axis, which was otherwise normally paired with the Y chromosome. Nucleolar material was associated with two bivalents and with the quadrivalent. CONCLUSIONS: The spermatocytes of heterozygotes for dependent Rb chromosomes formed a quadrivalent where four chromosomes are synapsed together and bound to the nuclear envelope through four telomeres. The nuclear configuration is determined by the fourth shortest telomere, which drags the centromere regions and heterochromatin of all the chromosomes towards the nuclear envelope, favouring the reiterated encounter and eventual rearrangement between the heterologous chromosomes. The unsynapsed regions of quadrivalents are frequently bound to the single axis of the X chromosome, possibly perturbing chromatin condensation and gene expression.

TERT Polymorphism rs2853669 Influences on Lung Cancer Risk in the Korean Population

Short telomeres are known as one of the risk factors for human cancers. The present study was conducted to evaluate the association between 6 polymorphisms, which were related with short telomere length in the Korean population, and lung cancer risk using 1,100 cases and 1,096 controls. Among the 6 polymorphisms, TERT rs2853669 was significantly associated with increased lung cancer risk under a recessive model (odds ratio [OR]=1.38, 95% confidence interval [CI]=1.05-1.81, P=0.02). The effect of rs2853669 on lung cancer risk was significant in younger individuals (OR=1.73, 95% CI=1.18-2.54, P=0.005) and adenocarcinoma (OR=1.50, 95% CI=1.07-2.07, P=0.02). Our results suggest that a common functional promoter polymorphism, TERT rs2853669, may influence both telomere length and lung cancer risk in the Korean population.

Telomerasa y telómero: su estructura y dinámica en salud y enfermedad / Telomerase and telomere: their structure and dynamics in health and disease

La telomerasa es la enzima responsable del mantenimiento de la longitud de los telómeros mediante la adición de secuencias repetitivas ricas en guanina, y su actividad se observa principalmente en gametos, células madre y células tumorales. En las células somáticas humanas el potencial de proliferación es limitado, alcanzando la senescencia luego de 50-70 divisiones celulares, debido a que la ADN polimerasa no es capaz de copiar el ADN en los extremos de los cromosomas. Por el contrario, en la mayoría de las células tumorales el potencial de replicación es ilimitado debido al mantenimiento de la longitud telomérica dado por la telomerasa. Los telómeros tienen proteínas adicionales que regulan la unión de la telomerasa. De la misma manera la telomerasa también se asocia con un complejo de proteínas que regulan su actividad. Este trabajo se centra en la estructura y función del complejo telómero/telomerasa y a cómo las alteraciones en su comportamiento conducen al desarrollo de diversas enfermedades, principalmente cáncer. El desarrollo de inhibidores del sistema telómero / telomerasa podría ser un blanco con posibilidades prometedoras.

Telomerase is the enzyme responsible for the maintenance of telomere length by adding guanine-rich repetitive sequences. Its activity can be seen in gametes, stem cells and tumor cells. In human somatic cells the proliferative potential is limited, reaching senescence after 50-70 cell divisions, because the DNA polymerase is not able to copy the DNA at the ends of chromosomes. By contrast, in most tumor cells the replicative potential is unlimited due to the maintenance of the telomeric length given by telomerase. Telomeres have additional proteins that regulate the binding of telomerase, likewise telomerase associates, with a protein complex that regulates its activity. This work focuses on the structure and function of the telomere/telomerase complex and how changes in its behavior lead to the development of different diseases, mainly cancer. Development of inhibitors of the telomere/telomerase complex could be a target with promising possibilities.

El nucléolo como un regulador del envejecimiento celular / The nucleolus as a regulator of cellular senescence

El nucléolo, considerado únicamente como el sitio de síntesis de los ribosomas, actualmente representa una estructura nuclear dinámica que participa en la regulación de importantes procesos celulares. Numerosas evidencias han demostrado que el envejecimiento celular es una de las diversas funciones que son controladas por el nucléolo. Las mutaciones en las proteínas de localización nucleolar promueven el envejecimiento prematuro en levaduras y humanos. La carencia de represión en la transcripción de genes que codifican para el ARNr que se encuentran dañados, y las mutaciones en las helicasas del ADN encargadas de minimizar la formación de círculos extra-cromosómicos del ADN que codifica para el ARNr, provocan modificaciones en la estructura del nucléolo e inducen envejecimiento prematuro en levaduras. De igual manera, en los humanos la carencia de las helicasas del ADN localizadas en el nucléolo y que participan en el mantenimiento de la integridad genómica, favorecen el desarrollo de aquellas enfermedades asociadas con el envejecimiento acelerado. Además, la presencia de algunos componentes de la telomerasa en el nucléolo, indica que parte de la biosíntesis de esta enzima se realiza en esta estructura nuclear, sugiriendo una conexión entre el nucléolo y la síntesis de los telómeros en la regulación del envejecimiento celular. Por otra parte, el nucléolo secuestra proteínas para regular su actividad biológica durante el inicio o término de la vida replicativa celular.

The nucleolus has been considered originally only as the site for the ribosome synthesis, but now it is well known that it represents a dynamic nuclear structure involved in important cellular processes. Several evidences have demonstrated that the nucleolus regulates the cellular senescence. Specific mutations on the DNAs codifying for nucleolar proteins induced premature senescence from yeast to human. The failure to repress the genes transcription codifying for damaged rRNA, and the mutations in DNA helicases, which minimizes the formation of DNA extra-chromosomal circles codifying for rRNA, modify the nucleolar structure and induce premature senescence in yeast. Similarly, in humans, the reduction of these DNA helicases levels, which are localized in the nucleoli and participate in maintenance of genomic integrity, helps to the development of those diseases associated with premature senescence. Furthermore, the presence in the nucleolus of some telomerase components, indicates that part of the biosynthesis of this enzyme occurred in this nuclear structure; suggesting a communication between the nucleolus and the synthesis of the telomeres in the regulation of cell senescence. On the other hand, the nucleolus sequesters proteins to regulate its own biological activity, from the start to the end of cellular replication. In addition this nuclear structure is involved in the biosynthesis of most cellular ribonucleoprotein particles, as well as in cell cycle regulation, making it central to gene expression. In conclusion, the nucleolus became a multifunctional subnuclear structure involved from cell proliferation to cell senescence.

The application of telomere DNA in age estimation of forensic medicine / 法医学杂志

Estimating tooth age and skeletal age are the two primary methods in age estimation of forensic medicine. But they are often impacted with geographical environment, nutrition, habitation and ethenologic differences, so the accuracy will be reduced, especially to the adult. With the study of telomere, it is certain that the length of the telomere DNA can reflect the cell division and represent the cell lifespan, and it has some pertinence to the age of the donor, so to measure the length of telomere DNA is a new and valuable method for age estimation in the forensic medicine.

Análisis molecular de la longitud telomérica en linfomas foliculares: Su participación en la progresón tumoral / Molecular analysis of telomere length in follicular lymphomas: Its participation in tumor progression

Los telómeros son estructuras esenciales para el mantenimiento de la integridad cromosómica y la capacidad replicativa de la célula. La reducción de la longitud telomérica (LT) aumenta la probabilidad de producir errores capaces de generar cambios genómicos importantes para el desarrollo neoplásico, determinando desbalances de material genético. En este trabajo se evaluó la LT mediante el análisis de fragmentos de restricción terminal (TRF) en médula ósea y/o biopsia ganglionar de 36 pacientes (edad media: 54.2 años; rango 29-77 años; 21 varones): 29 con linfoma folicular (LF) al diagnóstico y 7 con linfoma B difuso a células grandes secundario a LF (LBDCG-S). Se efectuó el análisis del rearreglo molecular del gen BCL-2 por PCR anidada y de larga distancia. Las medias de TRF en LF (4.18±0.18 Kb) y LBDCG-S (3.31±0.25 Kb) resultaron significativamente menores que en controles (8.50±0.50 Kb) (p<0.001), encontrándose diferencias entre ambos subtipos histológicos (p=0.036). Las muestras negativas para el rearreglo BCL-2 mostraron LT menores (3.39±0.30 Kb) que las positivas (4.25±0.19 Kb) (p=0.023), observándose una tendencia a valores menores en pacientes negativos para el rearreglo BCL-2, intermedios en positivos para mcr, minor cluster region, (3.84±0.45 Kb) y mayores en los positivos para MBR, Major Breakpoint Region, (4.35±0.21 Kb). Nuestros resultados muestran una reducción de la LT en LF y LBDCG-S, con TRFs significativamente más cortos en estos últimos, sugiriendo la participación del acortamiento telomérico em la progresión tumoral. Asimismo, las diferencias detectadas entre los casos BCL-2 positivos y negativos sustentarían la presencia de diferentes mecanismos patogénicos propuestos para estos distintos LF.

Study on the dynamic changing profiles of telomeric restricted fragment length among sex balanced different age groups / 法医学杂志

OBJECTIVE@#In human, both in vivo and in vitro, telomere shortening appears to be a major component of cell senescence and aging. The detailed telomere shortening status and mechanism in peripheral blood cell is needed to be further characterized.@*METHODS@#One hundred and twenty three peripheral blood samples were collected from healthy individuals of different age groups and the mean telomeric restricted fragment (TRF) was measured using Southern Blotting with Dig labeled probe. The samples of different groups were homogenized in sex components as indicated by chi 2 test of sex ratio of different test groups (P > 0.05).@*RESULTS@#The average length of TRF is shortening with aging and distinguished shortening dynamic profiles could be observed. Further analysis showed that there might be a shortening peak near the age of 5.@*CONCLUSION@#There are distinguished dynamics profiles of telomere shortening among different age groups. Thus, the results indicate that it might be possible to infer individual age by telomeric restricted fragment length assay.

Telómeros y telomerasas / Telomeres and telomerases

Los telómeros son estructuras cromatínicas especializadas que se encuentran localizadas en los extremos de los cromosomas eucariontes. Tanto el ADN como las proteínas que los constituyen presentan características singulares que los diferencian del resto de los cromosomas. Parecen estar implicados en numerosas funciones celulares, especialmente las relacionadas con el control de la duración de la vida de diferentes estirpes celulares. Estas estructuras se replican durante el ciclo celular gracias a la acción de enzimas denominadas telomerasas que están formadas por proteínas y ARN y presentan un mecanismo peculiar. Recientemente se ha estudiado el comportamiento de las telomerasas en las células cancerosas y sus posibles aplicaciones diagnósticas y terapéuticas. En este trabajo se presenta un resumen de los principales hallazgos más recientes sobre la estructura y funciones de los telómeros y la acción de las telomerasas

The role of telomeres and telomerase in human cancer.

Human cancers/malignant transformation of normal cells occur from multiple independent genetic changes/mutations that can subvert the normal growth controls of cells, leading to distinct phenotypic changes and immortalization. Normal human somatic cells have limited proliferative capacity both in vitro and in vivo and undergo senescence. Recent studies have implicated telomeres and telomerase in the regulation of lifespan of cells. Telomeres are the stretches of DNA consisting of tandem repeats of nucleotide sequences that cap chromosomes and prevent its degradation and play a role, both in normal control of cell proliferation and abnormal growth of cancers. They are highly conserved during evolution. Telomerase, the novel reverse transcriptase enzyme that synthesizes telomeric DNA is repressed in most human somatic cells, it results in telomere shortening with each cell division, leading to a process thought to contribute to senescence. Recent research proposes that activation of telomerase is important for cells to proliferate indefinitely and that all human cancer cells require activation of this enzyme to maintain telomeric DNA, to overcome cellular senescence and to attain immortality. Thus telomeres and telomerase offer potential for diagnostics, cancer therapy as well as for understanding the process of aging.