The adaptive molecular landscape of reprogrammed telomeric sequences

Telomeric sequences vary across the tree of life and intimately co-evolve with telomere-binding protein complexes. However, the molecular mechanisms allowing organisms to adapt to new telomeric sequences are difficult to gauge from extant species. Here, we engineer multiple yeast lines to human-like telomeric repeats to unveil their molecular and fitness response to reprogrammed telomeres. Initially, the exchange of telomere sequences results in genome instability, proteome remodelling and severe fitness decline. Adaptive evolution experiments select for repeated mutations that drive adaptation to the humanized telomeres. These consist of the recurrent amplification of the telomere-binding protein gene TBF1, by complex aneuploidies, or in repeated mutations that attenuate the DNA damage response. Overall, our results outline a response that defines the adaptive molecular landscape to reprogrammed telomeric sequences.