The main function of telomeres, which are big nucleoprotein complexes located in the extremes of the chromosomes, is to act as genomic buffers and support the erosion and reduction of DNA chromosomic ends that arise as a consequence of terminal replication. A minimal telomere length is also required in human reproduction in order to form a competent embryo.
To circumvent active DNA damage pathways that are prompted by critically short telomeres, cells must contend with the loss of telomere repeats due to various causes either by copying repeats using recombination pathways, or by synthesizing telomeric DNA “from scratch” using telomerase. The latter mechanism is found in most normal and malignant cells.
A role of the telomerase
Telomerase represents a combined ribonucleoprotein that contains both the reverse transcriptase telomerase protein and the telomerase RNA template as fundamental components. Furthermore, several other proteins are pivotal for telomerase assembly, its stability and localization within the nucleus.
Telomerase is proficient in adding telomere repeats (patterned by the telomerase RNA component) on the 3’ single-strand end of telomeres, thus it is no wonder its levels are consistently high in immortal cells (such as embryonic stem cells or cells of the germ line in the testis) with a constant telomere length.
Other important functions of telomerase have been discovered which are not necessary linked to telomere maintenance, such as the regulation of apoptosis and sensitizing mitochondrial DNA from oxidative damage induced by hydrogen peroxide, most probably by modulating mental homeostasis.
A telomerase-independent mechanism for length maintenance of telomeres is also described and known as the alternative lengthening of telomeres. The research indicates that this mechanism involves homologous recombination-mediated DNA replication with the support of the specific recombination complex that is found at normal human telomeres.
Telomere lengthening in embryos
After fertilization and activation of the human egg, a substantial telomere lengthening takes place in embryonic cells via alternative, telomerase-independent mechanism. This mechanism stays dominant in whole preimplantation development, and mouse models have shown that telomere length can increase by thousands of base-pairs within the initial one or two cell cycles.
But although recombination-based elongation of telomeres is happening during early preimplantation stage, the activity of telomerase increases considerably at the blastocyst stage of development. The biggest degree of telomere lengthening takes place in the inner cell mass, i.e. in the pluripotent cells.
Epigenetic states of the subtelomeric region can positively regulate telomere lengthening via recombination, which may someday result in improving reprogramming efficiency. Somatic cell nuclear transfer holds the promise of providing us with a platform for the production of personalized stem cells.