Telomeres, cell senescence and human ageing (original) (raw)
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Telomeres—structure, function, and regulation
Experimental Cell Research, 2013
In mammals, maintenance of the linear chromosome ends (or telomeres) involves faithful replication of genetic materials and protection against DNA damage signals, to ensure genome stability and integrity. These tasks are carried out by the telomerase holoenzyme and a unique nucleoprotein structure in which an array of telomere-associated proteins bind to telomeric DNA to form special protein/DNA complexes. The telomerase complex, which is comprised of telomeric reverse transcriptase (TERT), telomeric RNA component (TERC), and other assistant factors, is responsible for adding telomeric repeats to the ends of chromosomes. Without proper telomere maintenance, telomere length will shorten with successive round of DNA replication due to the so-called end replication problem. Aberrant regulation of telomeric proteins and/or telomerase may lead to abnormalities that can result in diseases such as dyskeratosis congenita (DC) and cancers. Understanding the mechanisms that regulate telomere homeostasis and the factors that contribute to telomere dysfunction should aid us in developing diagnostic and therapeutic tools for these diseases.
Telomeres: Chromosome End Protective-Complexes and Its Association with Chronic Diseases
2019
Telomeres are specialized nucleoproteins present at the end of linear eukaryotic chromosomes. They consist of a double-stranded DNA sequence and a single strand DNA protrusion (free 3'OH end). Telomeres are assembled into a three-dimensional structure in association with the shelterin complex. Telomeres play a central role in chromosomal stability and proliferative history of the cells. Shortening of telomeres is considered an important marker of cellular aging shortening in a physiological way in each round of cell replication in somatic cells. More impressive, telomeres' attrition is highly susceptible to deterioration related to DNA damage accumulation during the aging process. Clinical evidence suggests that telomeres' shortening contributes to the establishment and progression of the aging phenotype in some inflammatory chronic disorders. In other cases, experimental evidences suggest that aging is accompanied with an abrupt shortening in the context of such diseases, proposing that the length of telomeres may be an important biological marker for progression of various pathologies.
Telomere Biology: Telomere Structure, Function and Related Diseases
2020
Telomere is the special heterochromatin structure which caps the end of eukaryotic chromosome and ensures the faithful replication of genetic materials. It also provides the protection against DNA damage signals and ensures the genome integrity and stability. Telomerase complete its task by its unique nucleoprotein structure. Here in this paper detail about nucleoprotein structure and their function is included. Robustness of function of telomere across cell cycle is guaranteed by the interaction between telomere and its interacting proteins. Recent findings regarding telomere biology and cancer are also included in this paper.
Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts
Free Radical Biology and Medicine, 2000
Telomere shortening triggers replicative senescence in human fibroblasts. The inability of DNA polymerases to replicate a linear DNA molecule completely (the end replication problem) is one cause of telomere shortening. Other possible causes are the formation of single-stranded overhangs at the end of telomeres and the preferential vulnerability of telomeres to oxidative stress. To elucidate the relative importance of these possibilities, amount and distribution of telomeric single-strand breaks, length of the G-rich overhang, and telomere shortening rate in human MRC-5 fibroblasts were measured. Treatment of nonproliferating cells with hydrogen peroxide increases the sensitivity to S1 nuclease in telomeres preferentially and accelerates their shortening by a corresponding amount as soon as the cells proliferate. A reduction of the activity of intracellular peroxides using the spin trap ␣-phenyl-t-butyl-nitrone reduces the telomere shortening rate and increases the replicative life span. The length of the telomeric single-stranded overhang is independent of DNA damaging stresses, but single-strand breaks accumulate randomly all along the telomere after alkylation. The telomere shortening rate and the rate of replicative aging can be either accelerated or decelerated by a modification of the amount of oxidative stress. Quantitatively, stress-mediated telomere damage contributes most to telomere shortening under standard conditions.
The Journal of Pathology, 2009
Telomeres, the ends of eukaryotic chromosomes, have been the subject of intense investigation over the last decade. As telomere dysfunction has been associated with ageing and developing cancer, understanding the exact mechanisms regulating telomere structure and function is essential for the prevention and treatment of human cancers and age-related diseases. The mechanisms by which cells maintain telomere lengthening involve either telomerase or the alternative lengthening of the telomere pathway, although specific mechanisms of the latter and the relationship between the two are as yet unknown. Many cellular factors directly (TRF1/TRF2) and indirectly (shelterin-complex, PinX, Apollo and tankyrase) interact with telomeres, and their interplay influences telomere structure and function. One challenge comes from the observation that many DNA damage response proteins are stably associated with telomeres and contribute to several other aspects of telomere function. This review focuses on the different components involved in telomere maintenance and their role in telomere length homeostasis. Special attention is paid to understanding how these telomere-associated factors, and mainly those involved in double-strand break repair, perform their activities at the telomere ends.
Telomere biology in healthy aging and disease
Pflügers Archiv - European Journal of Physiology, 2010
Aging is a biological process that affects most cells, organisms and species. Telomeres have been postulated as a universal biological clock that shortens in parallel with aging in cells. Telomeres are located at the end of the chromosomes and consist of an evolutionary conserved repetitive nucleotide sequence ranging in length from a few hundred base pairs in yeast till several kilo base pairs in vertebrates. Telomeres associate with shelterin proteins and form a complex protecting the chromosomal deoxyribonucleic acid (DNA) from recognition by the DNA damagerepair system. Due to the "end-replication problem" telomeres shorten with each mitotic cycle resulting in cumulative telomere attrition during aging. When telomeres reach a critical length the cell will not further undergo cell divisions and become senescent or otherwise dysfunctional. Telomere shortening has not only been linked to aging but also to several age associated diseases, including tumorigenesis, coronary artery disease, and heart failure. In the current review, we will discuss the role of telomere biology in relation to aging and aging associated diseases.