Telomeres cap the ends of chromosomes and shorten with each cell division, one part of the collection of mechanisms that limits the lifespan of somatic cells that make up the bulk of our tissues. Fresh cells with long telomeres are regularly introduced by the stem cells that support each type of tissue in the body, while old cells that have divided many times destroy themselves or lapse into a state of senescence. Average telomere length in tissues tends to shorten with ill health and aging, and this is probably a consequence of reduced stem cell activity, among other factors. This picture is then complicated by the activity of telomerase, an enzyme that lengthens telomeres in various cell types to various degrees, and further by the less well understood process known as alternative lengthening of telomeres or ALT.
ALT is largely studied in the context of cancer. Cancerous cells are cancerous precisely because they can replicate without limits, and to do that they must be able to lengthen their telomeres constantly. A sizable fraction of cancers use ALT for this purpose, and so a way to selectively sabotage ALT should enable researchers to shut off many forms of cancer. Indeed, the SENS Research Foundation approach to cancer is the ambitious set of proposed treatments known as WILT, or whole-body interdiction of lengthening of telomeres. This would require blocking the telomere-lengthening activity of telomerase and sabotaging ALT permanently in all tissues, which in turn would require ways to selectively lengthen telomeres in stem cell populations on a regular basis so as to preserve tissue maintenance. Of all of the lines of SENS research, this is the one where the most remains to be discovered and the least is known of how exactly to achieve this end. Nonetheless, telomere lengthening is the single known shared point of vulnerability in all cancers at this time - strike at the root, as they say.
SENS or no SENS, plenty of cancer researchers would like to interfere in the operation of ALT, and progress is being made on the understanding needed to attain that goal:
Maintaining the ends of chromosomes, called telomeres, is a requisite feature of cells that are able to continuously divide and also a hallmark of human cancer. In a new study [researchers] describe a mechanism for how cancer cells take over one of the processes for telomere maintenance to gain an infinite lifespan. In general, cancer cells take over either type of telomere maintenance machinery to become immortal. Overall, approximately fifteen percent of cancers use the ALT process for telomere lengthening, but some cancer types use ALT up to 40 to 50 percent of the time.
The team showed that when DNA breaks, it triggers DNA repair proteins like the breast cancer suppressor protein BRCA2 into action, along with other helper proteins, that attach to the damaged stretch of DNA. These proteins stretch out the DNA, allowing it to search for complementary sequences of telomere DNA. "This process of repair triggers the movement and clustering of telomeres like fish being reeled toward an angler. The broken telomeres use a telomere on a different chromosome - the homologous telomere -- as a template for repair." In fact, in cancer cells that use ALT to maintain their telomeres, the team could visualize this process by imaging these clusters of telomeres coming together. The team would like to find other proteins involved in ALT and look for small molecule drugs that target this telomere maintenance mechanism in cancer cells to selectively kill cancer types that use ALT.
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multitelomere clusters and associated promyelocytic leukemia protein bodies.
Here, we show that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances.
This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.