Telomeres protect chromosomes from fusion and degradations, but this function is threatened in human somatic cells where telomeres are progressively shortened after successive cell divisions in the absence of telomerase activity. When telomeres are critically short, cells enter replicative senescence, in which the combined actions of the DNA damage signaling pathway, the DNA repair pathway, and mitosis mechanisms, can occasionally cause genomic instability and initiate oncogenesis. A difficulty associated with the study of mechanisms involved in genomic instability is the variability in telomere length, the intercellular variation in replicative senescence and the rarity of pathological events. The objective of this project is to study the initiation, expansion and consequences of genomic instability induced by telomere erosion. To circumvent the heterogeneity of genomic instability caused by telomere erosion, we are using a tool derived from CRISPR-Cas9 technology to generate telomeres of defined length in Saccharomyces cerevisiae. This tool will be used to study the global chromatin and epigenetic changes associated with telomere erosion that may contribute to the emergence of genomic instability.