Telomere Reprogramming and Cellular Metabolism: Is There a Link?

Abstract

Telomeres-special DNA-protein structures at the ends of linear eukaryotic chromosomes-define the proliferation potential of cells. Extremely short telomeres promote a DNA damage response and cell death to eliminate cells that may have accumulated mutations after multiple divisions. However, telomere elongation is associated with the increased proliferative potential of specific cell types, such as stem and germ cells. This elongation can be permanent in these cells and is activated temporally during immune response activation and regeneration processes. The activation of telomere lengthening mechanisms is coupled with increased proliferation and the cells' need for energy and building resources. To obtain the necessary nutrients, cells are capable of finely regulating energy production and consumption, switching between catabolic and anabolic processes. In this review, we focused on the interconnection between metabolism programs and telomere lengthening mechanisms during programmed activation of proliferation, such as in germ cell maturation, early embryonic development, neoplastic lesion growth, and immune response activation. It is generally accepted that telomere disturbance influences biological processes and promotes dysfunctionality. Here, we propose that metabolic conditions within proliferating cells should be involved in regulating telomere lengthening mechanisms, and telomere length may serve as a marker of defects in cellular functionality. We propose that it is possible to reprogram metabolism in order to regulate the telomere length and proliferative activity of cells, which may be important for the development of approaches to regeneration, immune response modulation, and cancer therapy. However, further investigations in this area are necessary to improve the understanding and manipulation of the molecular mechanisms involved in the regulation of proliferation, metabolism, and aging.

Keywords: ALT; OXPHOS; alternative lengthening of telomeres; development; glycolysis; metabolism; oxidative phosphorylation; telomerase; telomere.

Figure 2

Scheme of telomerase action at telomeres. Telomeric chromatin is organized in a closed state. Subtelomere DNA is methylated at CpG dinucleotides. Histones are characterized by heterochromatin modifications (H3K9me3 and H4K20me3), which are established by SUV39H1/2 and SUV4-20H1/2. Despite the heterochromatin status of telomeric regions, subtelomeric regions contain promoters that provide low-level transcription of the long non-coding RNA TERRA. The a-thalassemia/mental retardation syndrome and X-linked (ATRX) and death-domain-associated protein (DAXX) complex (ATRX/DAXX complex) stimulates the accumulation of H3.3 nucleosomes and prevents the homological recombination of telomeric regions. The shelterin complex, through TPP1, loads telomerase to the very end of the telomere and stimulates the synthesis of telomeric repeats in a processive manner, allowing the enzyme to translocate along the telomere and add more telomeric repeats after the synthesis of a single repeat.

Figure 3

ALTernative mechanism of telomere maintenance. Absence of ATRX at telomeres promotes recombination at telomeric chromatin. Repressive marks are reduced, and transcription of TERRA is stimulated, leading to putative recombinogenic DNA–RNA hybrids (R-loops). R-loops stimulate the formation of G-quadruplexes, leading to replication fork stalling followed by DNA damage response, activation of homology searching, and strand exchange, assisted by RAD51 and RAD52 accessory factors. After DNA synthesis, break-induced and/or homology-directed repair finalize the process of recombination. The accumulation of variant repeats in ALT cells resulting from telomere recombination can induce the binding of NR2C/F transcription factors to telomeres, leading to chromosomal rearrangements and genomic instability.

Figure 1

Human telomeric chromatin structure. The long double-stranded region of telomeric DNA is packed with nucleosomes in specific columnar arrangement and the very ends of telomeres are organized by the shelterin complex composed of telomeric repeat binding proteins 1 (TRF1) and 2 (TRF2), TRF1-interacting nuclear factor 2 (TIN2), TIN2-interacting protein (TPP1), protection of telomeres protein 1 (POT1), and repressor/activator site-binding protein 1 (RAP1). To prevent the degradation and reparation of chromosome ends, T-loops and D-loops protect telomeres. G-rich 3′-overhangs form G-quadruplex structures that stimulate telomerase to synthesize telomeric repeats and prevent the synthesis of the C-rich strand by the CTC1-STN1-TEN1 (CST) complex. Transcription of subtelomeric regions produces TERRA (TElomere Repeat containing RNA), which promotes R-loop formation stabilized by G-quadruplex structures at the opposite strand.

Figure 4

An overview of glucose metabolism. Glucose is catabolized in a series of enzymatic reactions yielding pyruvate. Pyruvate is converted in lactate or transported in mitochondria and metabolized by pyruvate dehydrogenase (PDH) into acetyl-CoA, fueling the tricarboxylic acid cycle (TCA). FBP—fructose biphosphate; 1,3-BPG—1,3-biphosphoglycerate; 3PG—3-phosphoglycerate; PEP—phosphoenolpyruvate. Glycolysis also fuels the pentose phosphate pathway, which produces nucleotides, amino acids, and fatty acids.

Figure 5

A schematic overview of spermatogenesis. Sertoli cells play an important role in energy and nutritional support of developing germ cells. Telomerase activity decreases during the differentiation of spermatogonia to mature spermatozoa, contributing to the elongation of telomeres.

Figure 6

A schematic overview of oogenesis. The maturation of oocytes is very sensitive to metabolism coordinated by the follicular cells. Telomerase activity decreases during oogenesis, providing the elongation of telomeres.

Figure 7

Telomere dynamics and metabolic program preferences during mouse embryo preimplantation development. During the first stage following fertilization, extensive chromatin remodeling occurs with histone-to-protamine replacement, the formation of two parental pronuclei and major zygotic genome activation (ZGA) at the two-cell stage, accompanied by the elongation of telomeres via a recombination-mediated mechanism that is telomerase-independent and involves the activation of the OXPHOS metabolism program. Then, at the stage following the morula–blastocyst transition, telomerase is activated. This process is characterized by a switch in the metabolism program from OXPHOS to glycolysis. In mouse zygotes, at the morula stage, ATRX is targeted to telomeres. The expression of H3K9 lysine demethylases from the Kdm4 family and Zscan4 favors telomere elongation through recombination in mouse and human zygotes.