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.