DNA serves as the fundamental instruction manual for all living organisms, guiding the development and function of every cell. This genetic blueprint is organized into chromosomes. To protect the ends of these chromosomes and maintain their stability, specialized caps known as telomeres are present. While telomeres typically shorten with each cell division, a process linked to cellular aging, some cells have developed alternative methods to preserve their telomere length. One such strategy is Alternative Lengthening of Telomeres (ALT).
The Role of Telomeres
Telomeres are specialized structures at the ends of linear chromosomes, acting as protective caps. They consist of repetitive DNA sequences, specifically thousands of repeats of the six-nucleotide sequence 5′-TTAGGG-3′ in humans, along with associated proteins. These nucleoprotein complexes shield chromosome ends from degradation, prevent them from fusing with other chromosomes, and ensure the cell’s DNA repair machinery does not mistakenly identify them as damaged DNA breaks.
During DNA replication, the “end-replication problem” leads to progressive shortening of telomeres with each cell division. As telomeres shorten beyond a certain point, cells can no longer divide and enter replicative senescence, effectively limiting a cell’s proliferative capacity. To counteract this natural shortening and allow for continued cell division, certain cells, such as germ cells and stem cells, utilize an enzyme called telomerase. Telomerase adds new telomeric DNA repeats to chromosome ends, maintaining telomere length and enabling indefinite proliferation.
Defining Alternative Lengthening of Telomeres
Alternative Lengthening of Telomeres (ALT) is a distinct mechanism that maintains telomere length without relying on telomerase enzyme activity. This pathway allows cells to bypass natural telomere shortening, enabling them to achieve cellular immortality.
Cells employing the ALT pathway exhibit several characteristic features. A hallmark of ALT cells is the pronounced heterogeneity in their telomere lengths; some telomeres can be exceptionally long, while others are very short. Another defining characteristic is the presence of extrachromosomal telomeric DNA circles, often referred to as C-circles. These small, circular DNA molecules are highly abundant in ALT-positive cells and serve as a reliable diagnostic marker for ALT activity.
How ALT Operates
The molecular mechanism underlying Alternative Lengthening of Telomeres primarily involves homologous recombination (HR). ALT cells utilize existing telomeres as templates to extend other telomeres, much like a “copy-and-paste” operation for DNA sequences. A shortened or damaged telomere end invades a longer telomere sequence on another chromosome or an extrachromosomal telomeric circle.
Once the invading telomere end finds a complementary sequence, it uses that longer telomere as a template to synthesize new telomeric DNA, thereby extending its own length. Specific DNA repair proteins orchestrate these recombination events, ensuring the accurate copying of the telomeric repeats. ALT activity is also associated with specialized nuclear structures called ALT-associated PML (promyelocytic leukemia) bodies (APBs). These nuclear foci are sites where telomeric DNA, telomere-binding proteins, and recombination factors congregate, facilitating the telomere lengthening process.
ALT’s Significance in Health and Disease
Alternative Lengthening of Telomeres holds significant implications, particularly in the context of human disease. While the majority of cancers reactivate telomerase to maintain their telomeres and achieve unlimited proliferation, a substantial subset of tumors relies on the ALT pathway. This mechanism allows these cancer cells to overcome the natural limits on cell division, contributing to their uncontrolled growth and the progression of the disease.
ALT is found in approximately 10-20% of all tumors, with particular prevalence in certain cancer types, including specific sarcomas like osteosarcomas and liposarcomas, as well as some gliomas and adrenal cortical carcinomas. Understanding ALT’s unique mechanisms is important because tumors that utilize this pathway often lack telomerase activity, making them potentially resistant to therapies designed to inhibit telomerase. Research into ALT aims to identify its specific molecular vulnerabilities, offering potential avenues for developing targeted anti-cancer drugs. These novel therapeutic strategies could specifically target ALT-dependent processes, providing treatment options for patients with ALT-positive tumors, which currently often have limited treatment choices beyond chemotherapy.