Telomeres

Telomeres are repetitive nucleotide sequences at the ends of linear chromosomes that protect genetic information during replication. In humans, telomeres consist of tandem repeats of the sequence TTAGGG, with a total length of several kilobases in germline cells and shorter lengths in most somatic cells. The ends form a T-loop structure and are bound by the shelterin protein complex, which protects chromosome ends from being recognized as DNA damage and regulates access of telomerase.

During DNA replication, the end-replication problem leaves the 3' overhang shorter after each cell division; nucleolytic processing and incomplete lagging-strand synthesis shorten telomeres. When telomeres reach a critically short length, cells enter replicative senescence or undergo apoptosis, contributing to aging. Telomere maintenance is accomplished by telomerase, a ribonucleoprotein enzyme that uses an RNA component (TERC) as a template to extend telomeric repeats at the ends, and a reverse transcriptase (TERT) catalytic subunit. Telomerase is active in most germ cells and stem cells, and frequently reactivated in cancer cells to enable limitless proliferation. About 85-90% of cancers rely on telomerase; a subset uses alternative lengthening of telomeres (ALT), a recombination-based mechanism independent of telomerase.

Telomere biology disorders, such as dyskeratosis congenita, involve mutations in telomere maintenance genes and manifest with hematologic or fibrotic diseases. Telomere length can be measured by various assays, including qPCR, Southern blot terminal restriction fragment analysis, and the TRAP assay for telomerase activity.