Telomere length and telomerase activity as biomarkers for diagnostics and prognosis of pathological disorders

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Abstract

Telomere biology research remains a hot topic. Analysis of several thousand clinical samples from healthy individuals performed in recent years has shown that the telomere length (TL) of peripheral blood leukocytes correlates with the TL of human internal organ cells and reflects their condition, decreases under the influence of damaging factors and can serve as an indicator of health status. A decrease in TL leads to proliferation arrest and is considered as an indicator of replicative aging of proliferating cells, and a decrease in TL of peripheral blood leukocytes is considered as an indicator of aging. Novel fundamental research data enabled to formulate the concepts about the role of the enzyme CST–Polymerase alpha/primase in the complementary C-strand synthesis after completion of the 3′G overhang synthesis by telomerase during telomere replication. The discovery of telomeric TERRA RNA and its role in the regulation of telomerase activity (TA) and alternative lengthening of telomeres, as well as the possibility of TERRA translation, provided evidence of the complex epigenetic regulation of TL maintenance. The published data analysis allows concluding that telomeres are dynamic structures and that TL undergoes significant changes under the influence of damaging factors and is determined not only by the chronological age, but by the total effect of exposure to all exogenous and endogenous damaging factors during the life. An inheritable decrease in TL due to mutations in the genes of proteins that determine the telomere structure and participate in the telomere replication, primarily the proteins of the shelterin complex, the CST complex and telomerase, has been found in a number of hereditary diseases – telomeropathies. Analysis of TL and TA is of great importance for the diagnosis of telomeropathies and may be useful in cancer diagnostics, and analysis of TL – for monitoring the health status, including exposure to ionizing radiation and space flight factors, together with the prediction of individual sensitivity to the action of damaging factors of different nature. The modern advanced genetic technologies for the analysis of TL and TA are available for use in clinical and epidemiological studies, are actively used in the telomeropathies diagnostics and astronauts’ health monitoring, and continue to improve.

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About the authors

E. Yu. Moskaleva

Kurchatov Complex of NBICS Nature-like Technologies, National Research Center “Kurchatov Institute”

Author for correspondence.
Email: Moskaleva_EY@nrcki.ru
Russian Federation, 123182 Moscow

A. I. Glukhov

I. M. Sechenov First Moscow State Medical University (Sechenov University); Lomonosov Moscow State University

Email: moskalevaey@mail.ru

Department of the Biological Chemistry, Faculty of Biology

Russian Federation, 119048 Moscow; 119991 Moscow

A. S. Zhirnik

Kurchatov Complex of NBICS Nature-like Technologies, National Research Center “Kurchatov Institute”

Email: moskalevaey@mail.ru
Russian Federation, 123182 Moscow

O. V. Vysotskaya

Kurchatov Complex of NBICS Nature-like Technologies, National Research Center “Kurchatov Institute”

Email: moskalevaey@mail.ru
Russian Federation, 123182 Moscow

S. A. Vorobiova

I. M. Sechenov First Moscow State Medical University (Sechenov University)

Email: moskalevaey@mail.ru

Department of the Biological Chemistry

Russian Federation, 119048 Moscow

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Supplementary files

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2. Fig. 1. Open telomere structure and T-loop telomere structure with D-loop formation in the region of single-stranded G-overhang insertion (a), and an example of telomere structure stabilization by shelterin complex proteins binding to double-stranded (TRF1 and TRF2) and single-stranded (POT1) telomeric DNA (b). Shelterin complex proteins cover the entire telomere. According to Griffith et al. [11] and de Lange [15]

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3. Fig. 2. The role of CST–Polα/Prim in telomere end DNA synthesis. Telomerase ensures the elongation of the G-overhang of the leading DNA strand, CST–Polα/Prim completes the complementary C-strand of the lagging and leading DNA strands at the telomere ends. When the replisome reaches the telomere end, synthesis of the last Okazaki fragment begins >40 nucleotides (nt) from the site of double-stranded DNA unwinding. Polδ and Polε are DNA polymerases δ and ε, respectively. According to Cai and de Lange [46]

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4. Fig. 3. Telomerase functions in the cell. Abbreviations: TERT and TR are the catalytic subunit and RNA component of telomerase, respectively; TERP is a protein transcribed from the TR template; TERRA (telomeric repeat containing RNA) is a long non-coding RNA with telomeric repeats 5`-UUAGGG-3′ at the 3`-end. Telomerase or the ALT pathway ensures the constancy of DT due to the synthesis of telomeric DNA, which is necessary for the formation of the T-loop and the preservation of chromosomes. In addition, the telomerase subunits TERT and TR have protective functions. TERT can migrate to mitochondria and increase the level of antioxidant protection and anti-apoptotic activity in these organelles. TR can serve as a template for the synthesis of the TERP protein, which exhibits anti-apoptotic activity. TERRA reduces AT and stimulates the ALT pathway to maintain DT

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5. Fig. 4. Mechanisms of AT reduction and DT reduction in cells under the influence of ionizing radiation and the development of oxidative stress in some pathological conditions. Abbreviations: ROS and AFS are reactive oxygen and nitrogen species, respectively; 8-OxodG is 8-oxo-7,8-dihydro-2′-deoxyguanosine; TERRA (telomeric repeat containing RNA) is a long non-coding RNA with telomeric repeats 5′-UUAGGG-3′ at the 3′ end; R-loops are hybrid RNA–DNA molecules that TERRA can form with the cytosine-rich strand of telomere DNA and cause displacement of the telomere DNA strand containing TTAGGG repeats.

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