Telomere Dysfunction Increases Mutation Rate and Genomic Instability
The increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined mutation rate in the absence of telomerase in S. cerevisiae. The mutation rate in the CAN1 gene increased 10- to 100- fold in est1 strains as telomeres became dysfunc- tional. This increased mutation rate resulted from an increased frequency of terminal deletions. Chromo- some fusions were recovered from est1 strains, sug- gesting that the terminal deletions may occur by a breakage-fusion-bridge type mechanism. At one lo- cus, chromosomes with terminal deletions gained a new telomere through a Rad52p-dependent, Rad51p- independent process consistent with break-induced replication. At a second locus, more complicated re- arrangements involving multiple chromosomes were seen. These data suggest that telomerase can inhibit chromosomal instability.
Telomere/genetics, Saccharomyces cerevisiae/genetics, Mutagenesis/genetics, Chromosome Aberrations/genetics, Amino Acid Transport Systems
Reprinted from Cell 106, Hackett, Jennifer A., et al, "Telomere Dysfunction Increases Mutation Rate and Genomic Instability", pg. 275-286, copyright 2001 with permission from Elsevier. Original version available at http://www.cell.com