Studies of the mechanism of recombinational telomere elongation in an alternative lengthening of telomere (ALT)-like Kluyveromyces lactis stn1-M1 mutant
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The generation and progression of most human cancers requires a telomere maintenance mechanism. While most cancers use telomerase to maintain telomeres, 5-10% maintain telomeres by a recombination-dependent mechanism termed alternative lengthening of telomeres (ALT). The telomeres in ALT cells are highly dynamic and display heterogeneous sizes ranging from barely detectable to highly elongated. However, the details of how telomeres change and are maintained in ALT cells are unknown. Here, we have studied the ALT-like telomere dynamics in the stn1-M1 mutant of the budding yeast Kluyveromyces lactis. The first study showed that telomeric circles (t-circles) could promote telomere elongation during both the establishment and the maintenance stages of the stn1-M1 state. It also characterized the dynamics of those telomeres. We found that they displayed constant changes of the size and the structure, as well as sometimes drastic loss or gain of telomeric sequences. Our data further suggest that the turnover of sequences involves a concerted amplification mechanism, an outcome consistent with copying t-circles. . In the second study, we examined telomere elongation during the establishment stage of the stn1-M1 state by using mutationally-tagged telomeric repeats. Our results suggested that before net telomere elongation occurred, telomeres first undergo a sudden shortening to lose the outermost telomeric repeats. Our results also showed that, as predicted by the roll-and-spread model, all elongated telomeres were commonly derived from sequence coming from a single telomere. Meanwhile, we also found that mismatch repair and telomerase had large effects on spreading of sequences from one mutationally-tagged telomere to others. Our study expands the knowledge of the mechanism of runaway recombinational telomere elongation in budding yeasts and provides clues to understand the mechanism of telomere generation and maintenance in ALT cells.