Alternative Lengthening of Telomeres

Alternative lengthening of telomeres (ALT) is a recombination process maintaining telomeric stability in the absence of telomerase. ALT is used by various types of cancer cells to bypass senescence. The significant role that ALT plays in human disease makes it important to understand how ALT is initiated, established, and maintained. However, the majority of studies in human cells models focus on ALT maintenance rather than establishment.  Saccharomyces cerevisiae yeast has been used as a robust model to study ALT establishment for decades. In particular, once telomerase is inactivated in yeast, one can study the process from the beginning of telomere shortening to the formation of ALT survivors. Studies in yeast have identified the phenotypes of ALT survivors, demonstrated the involvement of homologous recombination proteins, and suggested the mechanism of ALT proceeding via break-induced replication (BIR). We recently developed a population genetics-based quantitative assay to determine ALT frequency in telomerase deficient yeast. We were able to identify the role of genes during ALT based on their ALT frequencies. However, the lack of methods to characterize the structure of individual chromosomal ends during ALT hindered the understanding of ALT mechanism. In Malkova lab, we investigate the role of BIR genes in ALT, applying a novel system to track ALT from the very beginning to the formation of survivors and combing with Oxford Nanopore Technology (ONT) sequencing to determine the detailed structure of individual chromosome ends in each step of ALT.