Understanding the genetic requirements for the loss of end protection in the yeast Kluyveromyces lactis
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Telomeres are the DNA-protein caps that protect chromosome ends from being repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). The proper functioning of telomeres has been linked to helping prevent cancer and aging in humans. While the telomeres of most cells are maintained by the enzyme telomerase, some cells, including 5-10% of human cancers, utilize an alternate pathway to lengthen (ALT) their telomeres, thought to involve recombination. I have discovered that a mutation (stn1-M1), in a gene encoding a telomere binding protein in the yeast Kluyveromyces lactis, leads to elongated telomeres by engaging the recombinational telomere elongation (RTE) pathway. This mutant displays many characteristics similar to human ALT cells including long telomeres, abnormal growth, chronic telomeric capping defects, and extrachromosomal telomeric circles (t-circles) making it a useful model system for understanding ALT cells. In addition, we provide evidence for another consequence of a telomere-capping defect that lead to telomere fusions and are due to NHEJ. We demonstrate that the NHEJ proteins Mre11, Rad50, Ku80 and Ligase 4 have multiple roles at K. lactis telomere maintenance. Most notably, we saw for the first time that Ligase 4 contributes to protecting telomeres from HR. Thus, work from this study lends further support to the hypothesis that the capping function of telomeres is essential to prevent two major DNA repair pathways, HR and NHEJ, from acting at telomeres.