Molecule of the Month: Telomerase

Our cells must face a tricky problem: our machinery for DNA replication is not able to copy DNA strands to their very ends. Bacteria solve this problem in a simple way: their chromosomes are circular, so there aren’t any ends to cause problems. But complex eukaryotic cells store their genetic information in linear DNA strands, perhaps because it allows easier shuffling of genes during meiosis. So, they need a special mechanism to make sure the chromosomes don’t get shorter every time the cell divides.

The ends of our chromosomes are protected by a unique structure, called a telomere, composed of DNA and proteins. Telomeric DNA includes about a thousand repeats of the short sequence TTAGGG. Most of these repeated segments are paired with a complementary DNA strand to form a normal double helix, but several hundred nucleotides at the end are a single strand that is thought to loop back and interact with the double-stranded region. Several different types of proteins, collectively called “shelterin,” coat this telomeric DNA, protecting it.

The repeated nature of the telomere holds the solution to the end shortening problem: cells use telomerase to build new repeats when the telomere gets too short. Telomerase, seen here in PDB entry 6d6v, is a molecular machine that includes a template for the telomere repeat, and an enzyme that builds the repeat onto the end of chromosomes. The template is encoded in a short RNA strand (TER), which also includes non-coding regions that interact with the rest of the telomerase complex. The telomerase enzyme is a specialized reverse transcriptase (TERT) that uses this RNA template to create the telomere DNA. A collection of other proteins assist with the process, bringing telomerase to the telomere when it’s needed, and holding the telomere DNA end so that many repeats can be added in succession.

Telomerase is most active during development of embryos, when cells divide many times to create our entire body. Later in life, it is far less active in most cells, and telomeres gradually shorten as we age. Improper regulation of telomerase, however, can cause serious problems. For example, cancer cells very often have mutations that lead to production of higher levels of telomerase. This allows them to maintain their telomeres as they rapidly divide and form a tumor.

Structural biologists discovered that the guanine-rich sequence of telomeres can form an unusual structure. Four guanines come together to form a quadruplex structure. As seen in PDB entry 143d, a DNA strand with four telomere repeats can form a tight little knot, with the G-quadruplexes tucked inside.