A unified alternative telomere lengthening pathway in yeast survivor cells
Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase, and is an important survival mechanism for cancer cells. Yeast has been used as a robust model of ALT; however, the inability to determine the frequency and chromosomal structure of ALT hindered the understanding of its mechanism. Here, using populational and molecular genetics approaches we overcome these problems and demonstrate that, contrary to the current view, both RAD51 -dependent and -independent mechanisms are required for a single ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies as well as on ultra-long sequencing of ALT products that revealed “hybrid” sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrate that recombination begins with RAD51 -mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. We propose that similar to yeast, a single major pathway may be driving ALT in other organisms including humans.