Location and function of telomeres

Telomeres are composed of nucleotides and are located at the end of chromosomes in eukaryotic cells. They cap the termination of the double strands of DNA and thus preserve the integrity and stability of the genome during replication . Telomeres are made up of a repetitive sequence of six nitrogenous bases rich in guanine (TTAGGG). This sequence is repeated over several thousand base pairs at the 3′ end of DNA (4 to 15 kilobases in humans). In most human somatic cells, the length of the telomeres decreases by 20 to 200 base pairs with each cell division. This loss of genetic material corresponds to the phenomenon called “the end replication problem”. If this shortening of telomeres is not repaired, it eventually leads to cessation of the cell cycle and cell death by apoptosis . The synthesis of telomere DNA requires the activity of specialized enzyme complexes: telomerases. These complexes are made up of various proteins (TRAF1, TRAF2, Ku86, TIN2, etc.) . Their function is to lengthen telomeres by the synthesis of two supplementary TTAGGG sequences at their ends. Typically, telomerase activity is diminished or even absent in most adult somatic cells, the exception being cells with a strong potential for division, like active lymphocytes and certain types of stem cells .

Regulation of telomere length

The maintenance of telomere length depends on several factors, including the composition in associated proteins, the level of oxidative stress and the level of telomerase activation as well as telomere length itself . This is why telomere length varies considerably from one species to another and from one individual to another. Moreover, it seems that telomere length may be affected by certain genetic factors, notably linked to chromosome X : this was shown in a study by Nawrot et al. in 2004 involving a cohort of families.

Telomerase activity, however, seems to be one of the key elements in the maintenance of telomere integrity. Indeed, cells with short telomeres and an absence of telomerase activity become senescent and go into apoptosis more quickly than do cells with telomeres that are long enough not to require telomerase activity to survive . Inversely, some cells are deficient in TERC, TERT and other proteins necessary for telomerase function. This is illustrated by the transfection of primary B and T lymphocytes from patients with dyskeratosis congenita with exogenous TERC, which restored telomerase activity and increased telomere length .

Moreover, the role of the Rad54, which is involved in DNA repair, in the regulation of telomere length was brought to light recently. Indeed, Rad54-deficient mice presented severe telomere shortening, and this in the absence of any modification in telomerase activity . These findings tend to show that Rad54 protein is involved in a mechanism that maintains the integrity of telomeres independently of telomerases.

The regulation of telomere length also depends on the level of methylation of certain histones, namely histones H3 and H4, associated with subtelomeric regions. The methylation of these histones decreases access to telomere sequences and thus diminishes telomerase activity . Therefore, proteins that play a role in the regulation of these methylations have an impact on telomere length. For example, proteins of the retinoblastoma family increase the methylation of subtelomeric regions and thus diminish telomere length . In contrast, retinoblastoma protein 2, which depresses the activity of DNA methytransferase, responsible for the methylation of subtelomeric regions, plays a role in increasing telomere length .

The existence of telomeric RNA (called TERRA or TelRNA), which is transcribed by RNA polymerase II, has been shown recently. These telomeric RNA transcriptions may have a negative impact on telomere length . Finally, one of the major mechanisms of telomere shortening is the activity of exonucleases 5′-3′ . Indeed, the role of these exonucleases is to degrade the RNA primer used in the replication of the DNA necessary for DNA polymerase activity. This deterioration creates lesions in which the DNA is in the single strand form within the replication loop. The presence of single-strand DNA prevents the formation of Okazaki fragments and thus elongates the DNA, but can lead to an increase in: damage to DNA; the risk of fusion of chromosome extremities ; and the activation of p53-dependent responses to DNA damage .

The maintenance of telomere length within eukaryotic cells is thus a complex phenomenon that involves a wide range of factors. Several mechanisms acting in a synergistic fashion thus appear to stabilize telomere length. The different mechanisms mentioned above involved in the regulation of telomere length are shown schematically in Fig. 1 .

Schematic representation of telomere structure in the eukaryotic cell and the principal mechanisms involved in the regulation (positive or negative) of telomere length. AP-1: activator protein 1; ATM: ataxia telangiectasia muted; c-Fos: cellular proto-oncogene belonging to the immediate early gene family of transcription factors; c-Jun: a gene, which in combination with c-Fos, forms the AP-1 early response transcription factor; DNMT: DNA methyltransferase; h-TERT: human telomerase reverse transcriptase; Me: methyl; Rad54: eukaryotic homologue of the prokaryotic RecA protein 54; Rb: retinoblastoma; Rbl2: retinoblastoma protein 2; RNA: ribonucleic acid; TERC: telomerase RNA component; TERRA or TelRNA: telomeric RNA; TIN2: TATA binding protein-related factor 1 (TRF1)-interacting nuclear protein 2; TRAF1: tumour necrosis factor receptor-associated factor 1; TRAF2: tumour necrosis factor receptor-associated factor 2; TRF2: TATA binding protein-related factor 2.