Telomere Biology and Human Phenotype

Abstract

Telomeres are nucleoprotein structures that cap the end of each chromosome arm and function to maintain genome stability. The length of telomeres is known to shorten with each cell division and it is well-established that telomere attrition is related to replicative capacity in vitro. Moreover, telomere loss is also correlated with the process of aging in vivo. In this review, we discuss the mechanisms that lead to telomere shortening and summarise telomere homeostasis in humans throughout a lifetime. In addition, we discuss the available evidence that shows that telomere shortening is related to human aging and the onset of age-related disease.

Telomeres and Telomere Length: A General Overview

“…DNA polymerase Polα with a single RNA primer initiates the synthesis of a new strand in 5 to 3 direction towards replication fork, which is subsequently replaced by Polε for further elongation, forming the "leading strand" [86,87]. The synthesis of the "lagging strand" in the 5 to 3 direction requires annealing of multiple primers that elongate into short Okazaki fragments opposite to the replication fork and occurs less efficiently than the leading strand [88,89]. On completion of replication, the primer degradation results in internal gaps, filled by the polymerase, Polδ, and ligated to form a continuous strand.…”

“…On completion of replication, the primer degradation results in internal gaps, filled by the polymerase, Polδ, and ligated to form a continuous strand. The gap left by the primer degradation at the terminal end remains unfilled, which results in the loss of a short segment of DNA at the 5 end of the lagging strand [89]. The lagging strand synthesis fails to replicate an average length of~250 nucleotides at the end of linear templates, which is hypothesized due to an inability of DNA Polα-primase to initiate lagging strand synthesis from the very end of linear DNA [90].…”

“…The loss of nucleotides at the chromosomal end leads to the G-rich single strand (Figure 4) at the end of the telomeres and, according to one hypothesis, the size of the 3 overhang is determinant of the rate of telomere shortening [91]. Normal human cells in a culture stop dividing after 40 to 60 passages, a phenomenon first observed by Leonard Hayflick and eponymously called the Hayflick limit [89,92]. Incomplete replication with a gradual shortening of telomeres acts as a counting mechanism that eventually leads to the replicative senescence [93].…”

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications

“…This telomere-associated protein complex is composed of six individual factors. The three main components are the telomeric repeat binding factor 1 (TRF1) and 2 (TRF2), that bind to double-stranded telomeric DNA, and the protection of telomeres 1 (POT1), which binds directly to single-stranded telomeric sequences [1][2][3]. These proteins interact with additional factors, such as the TRF1-interacting protein 2 (TIN2), the ACD shelterin complex subunit and telomerase recruitment factor (ACD; formerly known as POT1-and TIN2-organizing protein, TPP1), and the transcriptional repressor/activator protein 1 (TERF2IP, also known as Rap1) [1][2][3].…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…Telomere. Telomeres, composed of the telomere DNA sequence and telomere protein, are nucleoprotein structures located at the end of chromosomes, which control the cell division cycle and maintain the genome's integrity [83].…”