Telomeres and telomerase provide protection against threats to the genome that arise from a difficulty inherent in the asymmetric replication of DNA. Without telomeres, genetic material would be lost every time a cell divides. DNA polymerase requires an RNA primer with a 3′ hydroxyl donor group to initiate DNA replication, during which the “end-replication problem” arises.5
The primer dissociates as the DNA polymerase moves along the template strand, leaving behind a gap at the ends of chromosomes. As a result, the newly synthesized DNA strand is shorter than the original template. Telomeres and telomerase ameliorate this problem by providing a repetitive template for enzymatic repair of the ends of chromosomes, thereby avoiding the loss of genetically encoded information during mitosis.
Telomeres consist of repetitive DNA sequences coated by capping proteins (shelterin) at the ends of linear chromosomes (). In human cells, telomeres consist of hundreds to thousands of TTAGGG tandem repeats in the leading strand.7
A single-stranded 3′-hydroxyl overhang is generated by the catalytic addition of telomeric repeats to the 3′ end and by postreplicative processing of the lagging strand. Shelterin proteins, which coat the telomeric DNA sequence,8
serve as a molecular signal to prevent the cellular DNA repair machinery from mistaking telomeres for double-stranded DNA breaks.
When they are too short, telomeres signal the arrest of cell proliferation, senescence, and apoptosis. This process explains the interruption of proliferation in cultured human cells — the “Hayflick limit” ().9
If protective mechanisms, such as the TP53
tumor-suppressor gene, are inactive, thus allowing continued proliferation, telomeres become extremely short and dysfunctional; end-to-end fusions ultimately cause chromosomal instability. Conversely, cells transfected with the telomerase gene can proliferate indefinitely.10
Consequences of Telomere Erosion in the Cell
To avoid the attrition of telomeres, germ-line cells and some somatic cells produce telomerase, an enzyme that catalyzes DNA synthesis to maintain telomere length. Telomerase reverse transcriptase (TERT) uses the telomerase RNA component (TERC) as a template to synthesize telomere DNA (). The catalytic unit of telomerase contains two copies each of TERT, TERC, and dyskerin (encoded by the DKC1 gene), and proteins that stabilize the complex.
The Telomerase Complex and Its Components
Telomerase has functions other than elongating telomeres.11
For example, telomerase over-expression in adult mice mobilizes stem cells and induces stem-cell proliferation in the absence of telomere elongation by modulation of the wingless in drosophila (Wnt)–β
-catenin signaling pathway.12
Mice in which telomerase genes have been knocked out have been used to model the role of these genes in higher organisms. However, differences in telomere biology between mice and humans preclude ideal modeling of human biology in the mouse system. Moreover, in contrast to mice in the wild, laboratory strains have very long telomeres, and the first generation of telomerase-knockout mice does not show critical telomere shortening or a phenotype. Tissue abnormalities usually appear after the fifth generation; by the sixth generation, mice are infertile and hematopoietic progenitor function is defective.