The Balancing Act of Telomere Maintenance
Telomeres, the end caps of a chromosome, protect the immediately adjacent genes from deterioration and prevent fusions with other chromosomes. During replication, DNA polymerases fail to replicate the final few hundred base pairs of a DNA strand. Lacking genes themselves, telomeres consist of repetitive nucleotide sequences (5'-TTAGGG-3' in mammals) that are cumulatively degraded during each round of cell division, thereby protecting the precious end genes from a similar fate1.
The repetitive DNA sequences of telomeres are added by the catalytic subunit (Tert) of the reverse transcriptase telomerase2. The majority of a telomere is composed of double-stranded DNA, with the exception of the single-stranded 3' overhang that forms a lariat structure termed a t-loop3. A number of telomere-binding proteins and their associated interacting proteins (e.g. Trf1, Trf2, Tin2, Tpp1, Pot1, and Rap1) are found within the t-loop, where they maintain the structure and function of the telomere and participate in the replication of telomeric DNA2, 4.
The eventual erosion of a telomere over the lifetime of a cell results in cellular senescence or apoptosis. Due to the cumulative nature of this process, telomere shortening is thought to be a biomarker of normal aging, and premature telomere shortening has been implicated in a number of health conditions, including chronic stress, chronic infection, and DNA damage repair syndromes such as ataxia telangiectasia1, 5.
Telomere shortening also guards against uncontrolled cell division. The overexpression of telomerase can induce cell immortalization, and, conversely, downregulation of telomerase activity induces apoptosis3. Thus, telomerase inhibitors are of interest as potential cancer therapeutics, although some studies suggest that cancer cells treated with a telomerase inhibitor find alternative ways of maintaining their telomeres, in a process aptly known as alternative lengthening of telomeres (ALT)6.
Contributed by Allison A. Curley, Ph.D.
Below is the entire list of targets involved with mRNA Processing: