The lengths of telomeres, which are caps for chromosome ends, are kept consistent by a pathway that “counts” the number of Rap1 molecules bound to telomeres. This pathway signals through Tel1 to recruit the lengthening telomerase enzyme. Cells missing Tel1 have shorter but stable telomeres, which argues for a second pathway regulating length. Searching for clues to the second pathway, Florence Hediger, Susan Gasser (Friedrich Miescher Institute, Basel, Switzerland), and colleagues focused on the proximity of different telomeres to the nuclear envelope (NE)—one place telomerase is thought to concentrate.
Her team shows that the anchoring of individual telomeres near the NE is variable and correlates with the composition of the subtelomeric DNA sequence elements (STEs). The less-anchored telomeres had two STEs with multiple binding sites for Reb1 and Tbf1, factors previously shown to act as insulators against telomere-associated gene silencing. Artificial binding of Reb1 and Tbf1 to normally stably anchored telomeres can also release them from the NE.
Enter Anne-Sophie Berthiau, Eric Gilson (Ecole Normale Supérieure, Lyon, France), and colleagues. They showed that Reb1 and Tbf1 artificially bound to subtelomeric regions causes shortening of telomeres, with more Reb1 and Tbf1 binding sites causing more shortening.
“Our data and Eric's together argue that this pathway, which is not using Rap1-Tel1 signaling, may have more to do with proximity and accessibility of telomeres to telomerase,” says Gasser. She proposes that the binding of STE factors changes the folding of telomeres, and subsequently their accessibility or proximity to telomerase.
Concentrating telomerase at a membrane might keep it at a low, but effective, amount. Cells need a critical amount of it, but if they get too much then telomeres might get added anywhere a double-stranded DNA break occurs.