A mechanism for telomere-specific telomere length regulation

Telomere length is a critical determinant of telomere function and hence chromosome stability. Critically short telomeres induce cellular senescence and division arrest, which eventually may lead to devastating age-related degenerative diseases. Conversely, maintenance of telomere length is a hallmark of cancer. How telomere set-length is established and molecular mechanisms for telomere-specific length regulation remained unknown. Here, we detail a mechanism of a telomere-specific set-length regulation that causes important differences in telomere length between individual telomeres in the same cell. Indeed, the results show that telomerase recruitment is modulated in cis in a telomere-specific way. Increased Sir4 abundance on yeast TEL03L subtelomeric heterochromatin leads to a set-length maintenance that is 1.5 to 2 times higher than on other telomeres. Remarkably, the distal 15 kb of TEL03L are sufficient to transfer this telomere-specific set-length regulation to another chromosome end. Furthermore, a mutation in the telomere boundary element protein Tbf1 allow increased Sir4 binding on telomeres and hence results in longer set-lengths. The results, therefore, will force a rethinking of telomere length regulation away from the generalized view that all telomeres are treated the same, to a more telomere-specific treatment.