Abstract
The phenomenon of gradual telomere shortening has become a paradigm for how we understand the biology of aging and cancer. Cell proliferation is accompanied by cumulative telomere loss, and the aged cell either senesces, dies or transforms toward cancer. This transformation requires the activation of telomere elongation mechanisms in order to restore telomere length such that cell death or senescence programs are not induced. Most of the time, this occurs through telomerase reactivation. In other rare cases, the Alternative lengthening of telomeres (ALT) pathway hijacks DNA recombination-associated mechanisms to hyperextend telomeres, often to more than 50 kb. Why telomere length is restricted and what sets their maximal length has been a long-standing puzzle in cell biology. Two recent studies published in this issue of EMBO Reports [1] and recently in Science [2] sought to address this important question. Both built on omics approaches that identified ZBTB48 as a potential telomere-associated protein and reveal it to be a critical regulator of telomere length homeostasis by the telomere trimming mechanism. These discoveries provide fundamental insights for our understanding of telomere trimming and how it impacts telomere integrity in stem and cancer cells.