Telomerase
Telomerase, also called terminal transferase,[1] is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.[2]
Telomerase is a reverse transcriptase enzyme that carries its own RNA molecule (e.g., with the sequence 3′-CCCAAUCCC-5′ in Trypanosoma brucei)[3] which is used as a template when it elongates telomeres. Telomerase is active in gametes and most cancer cells, but is normally absent in most somatic cells.
History[edit]
The existence of a compensatory mechanism for telomere shortening was first found by Soviet biologist Alexey Olovnikov in 1973,[4] who also suggested the telomere hypothesis of aging and the telomere's connections to cancer and perhaps some neurodegenerative diseases.[5]
Telomerase in the ciliate Tetrahymena was discovered by Carol W. Greider and Elizabeth Blackburn in 1984.[6] Together with Jack W. Szostak, Greider and Blackburn were awarded the 2009 Nobel Prize in Physiology or Medicine for their discovery.[7] Later the cryo-EM structure of telomerase was first reported in T. thermophila, to be followed a few years later by the cryo-EM structure of telomerase in humans.[8]
The role of telomeres and telomerase in cell aging and cancer was established by scientists at biotechnology company Geron with the cloning of the RNA and catalytic components of human telomerase[9] and the development of a polymerase chain reaction (PCR) based assay for telomerase activity called the TRAP assay, which surveys telomerase activity in multiple types of cancer.[10]
The negative stain electron microscopy (EM) structures of human and Tetrahymena telomerases were characterized in 2013.[11][12] Two years later, the first cryo-electron microscopy (cryo-EM) structure of telomerase holoenzyme (Tetrahymena) was determined.[13] In 2018, the structure of human telomerase was determined through cryo-EM by UC Berkeley scientists.[14]
Mechanism[edit]
The shelterin protein TPP1 is both necessary and sufficient to recruit the telomerase enzyme to telomeres, and is the only shelterin protein in direct contact with telomerase.[24]
By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-TTAGGG (in vertebrates; the sequence differs in other organisms) to the 3' strand of chromosomes. These TTAGGG repeats (with their various protein binding partners) are called telomeres. The template region of TERC is 3'-CAAUCCCAAUC-5'.[25]
Telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process. Telomerase reverses telomere shortening.
Clinical implications[edit]
Aging[edit]
Telomerase restores short bits of DNA known as telomeres, which are otherwise shortened after repeated division of a cell via mitosis.
In normal circumstances, where telomerase is absent, if a cell divides recursively, at some point the progeny reach their Hayflick limit,[26] which is believed to be between 50 and 70 cell divisions. At the limit the cells become senescent and cell division stops.[27] Telomerase allows each offspring to replace the lost bit of DNA, allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of cancerous growth.[28]
Embryonic stem cells express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed only in cells that need to divide regularly, especially in male sperm cells,[29] but also in epidermal cells,[30] in activated T cell[31] and B cell[32] lymphocytes, as well as in certain adult stem cells, but in the great majority of cases somatic cells do not express telomerase.[33]
A comparative biology study of mammalian telomeres indicated that telomere length of some mammalian species correlates inversely, rather than directly, with lifespan, and concluded that the contribution of telomere length to lifespan is unresolved.[34] Telomere shortening does not occur with age in some postmitotic tissues, such as in the rat brain.[35] In humans, skeletal muscle telomere lengths remain stable from ages 23 –74.[36] In baboon skeletal muscle, which consists of fully differentiated postmitotic cells, less than 3% of myonuclei contain damaged telomeres and this percentage does not increase with age.[37] Thus, telomere shortening does not appear to be a major factor in the aging of the differentiated cells of brain or skeletal muscle. In human liver, cholangiocytes and hepatocytes show no age-related telomere shortening.[38] Another study found little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities.[39]
Some experiments have raised questions on whether telomerase can be used as an anti-aging therapy, namely, the fact that mice with elevated levels of telomerase have higher cancer incidence and hence do not live longer.[40] On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan.[41] A study found that long-lived subjects inherited a hyperactive version of telomerase.[42]