the end-replication problem and telomerase

There is a built-in catch with copying a linear chromosome that has two open ends, like the ends of a shoelace. Because the lagging strand needs an RNA primer to start each piece, the very last primer at the chromosome's end leaves a gap once it is removed — and there is nowhere upstream to lay a new primer to fill it. So a little bit of the end fails to get copied, and the chromosome would get shorter with every division. This is the end-replication problem.

Cells protect their chromosome ends with telomeres — long stretches of a short repeated sequence (in humans, TTAGGG repeated thousands of times) that carry no genes, so the shortening eats into disposable buffer rather than important DNA. The solution to actually rebuilding the lost ends is an enzyme called telomerase. Telomerase is a reverse transcriptase that carries its own short RNA template; it uses that built-in RNA to add telomere repeats back onto the chromosome's 3' end, extending it so the lagging-strand machinery can fill in behind. In effect it carries its own primer-template and counteracts the shortening.

Telomerase is highly active in germ cells, stem cells, and single-celled organisms, but it is switched off in most ordinary human body cells. So those cells' telomeres shorten with each division until they get critically short and the cell stops dividing (senescence) — a contributor to aging, though far from its only cause. The flip side is dangerous: most cancers reactivate telomerase, removing this natural limit and helping the tumour divide without end. Telomerase thus sits at a fascinating crossroads of aging and cancer, and its discovery earned a Nobel Prize.